Handbook of Schizophrenia Spectrum Disorders, Volume III
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(12) Patent Application Publication (10) Pub. No.: US 2017/0020892 A1 Thompson Et Al
US 20170020892A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0020892 A1 Thompson et al. (43) Pub. Date: Jan. 26, 2017 (54) USE OF NEGATIVE MODULATORS OF Related U.S. Application Data GABA RECEPTORS CONTAINING ALPHAS SUBUNITS AS FAST ACTING (60) Provisional application No. 61/972,446, filed on Mar. ANTDEPRESSANTS 31, 2014. (71) Applicant: University of Maryland, Baltimore, Publication Classification Baltimore, MD (US) (51) Int. Cl. A 6LX 3/557 (2006.01) (72) Inventors: Scott Thompson, Baltimore, MD (US); A6II 3/53 (2006.01) Mark D. Kvarta, Ellicott City, MD A6II 45/06 (2006.01) (US); Adam Van Dyke, Baltimore, MD (52) U.S. Cl. (US) CPC ........... A61 K3I/55.17 (2013.01); A61K 45/06 (2013.01); A61 K3I/53 (2013.01) (73) Assignee: University of Maryland, Baltimore, Baltimore, MD (US) (57) ABSTRACT Embodiments of the disclosure include methods and com (21) Appl. No.: 15/300,984 positions related to treatment of one or more medical conditions with one or more negative modulators of GABA (22) PCT Filed: Mar. 31, 2015 receptors. In specific embodiments, depression and/or Sui cidability is treated or ameliorated or prevented with one or (86) PCT No.: PCT/US2O15/023667 more negative modulators of GABA receptors, such as a S 371 (c)(1), partial inverse agonist of a GABA receptor comprising an (2) Date: Sep. 30, 2016 alpha5 subunit. Patent Application Publication Jan. 26, 2017. Sheet 1 of 12 US 2017/002O892 A1 ×1/ /|\ Patent Application Publication Jan. 26, 2017. Sheet 3 of 12 US 2017/002O892 A1 & Patent Application Publication Jan. -
Bifeprunox: a Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT1A Receptors
DRUG EVALUATION Bifeprunox: a novel antipsychotic agent with partial agonist properties at dopamine D2 and serotonin 5-HT1A receptors Marie-Louise G Most second-generation, atypical, dopamine (DA) D2/5-HT2 blocking antipsychotics still Wadenberg induce extrapyramidal side effects (EPS) in higher doses. Weight gain and metabolic University of Kalmar, disturbances are also a problem, and negative and cognitive symptoms have not been Department of Natural Sciences, Norra Vagen 49, sufficiently addressed. The current brain DA mesolimbic hyperactive/mesocortical SE-391 82 Kalmar, Sweden hypoactive hypothesis of schizophrenia suggests that DA D2/5-HT1A receptor partial agonist Tel.: +46 480 446 277; properties may be more efficacious with less side effects. DA D2 receptor partial agonists Fax: +46 480 446 244; may stabilize a hyperactive/hypoactive DA condition. Additional 5-HT stimulation may marie-louise.wadenberg@ 1A hik.se enhance therapeutic efficacy and also improve EPS liability profile. In clinical trials in schizophrenic patients, the novel DA D2/5-HT1A partial agonist bifeprunox indeed demonstrates therapeutic efficacy, a safe EPS profile and appears beneficial regarding weight gain, prolactin, blood lipid and glucose levels and cardiac rhythm. The data on bifeprunox are promising and suggest that combined DA D2/5-HT1A partial agonism may well be important properties for future-generation antipsychotics. Bifeprunox, a novel antipsychotic agent with a (DA D1, D2, D4, 5-HT2A/C, 5-HT1A, hista- so-called third-generation atypical pharmacolog- mine H1, α1, α2, cholinergic muscarinic recep- ical profile, is currently in clinical trials and tor affinity) and comparatively lower affinity for expected to launch as a schizophrenia therapy in the DA D2 receptor than traditional APDs. -
HTR1A Polymorphisms and Clinical Efficacy Of
International Journal of Neuropsychopharmacology, (2016) 19(5): 1–10 doi:10.1093/ijnp/pyv125 Advance Access publication November 14, 2015 Research Article research article HTR1A Polymorphisms and Clinical Efficacy of Antipsychotic Drug Treatment in Schizophrenia: A Meta-Analysis Yoshiteru Takekita, MD, PhD; Chiara Fabbri, MD; Masaki Kato, MD, PhD; Yosuke Koshikawa, MA; Aran Tajika, MD; Toshihiko Kinoshita, MD, PhD; Alessandro Serretti, MD, PhD Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (Drs Takekita, Fabbri, and Serretti); Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan (Drs Takekita, Kato, Koshikawa, and Kinoshita); Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan (Dr Tajika). Correspondence: Yoshiteru Takekita, MD, PhD, Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Viale Carlo Pepoli 5, Bologna, 40123, Italy ([email protected]). Abstract Background: This meta-analysis was conducted to evaluate whether HTR1A gene polymorphisms impact the efficacy of antipsychotic drugs in patients with schizophrenia. Methods: Candidate gene studies that were published in English up to August 6, 2015 were identified by a literature search of PubMed, Web of Science, and Google scholar. Data were pooled from individual clinical trials considering overall symptoms, positive symptoms and negative symptoms, and standard mean differences were calculated by applying a random-effects model. Results: The present meta-analysis included a total of 1281 patients from 10 studies. Three polymorphisms of HTR1A (rs6295, rs878567, and rs1423691) were selected for the analysis. In the pooled data from all studies, none of these HTR1A polymorphisms correlated significantly with either overall symptoms or positive symptoms. -
An Investigation Into Pro-Apoptotic Targets in Experimental Glaucoma and the Neuroprotective Effects of Ginkgo Biloba in Retinal Ganglion Cells
An investigation into pro-apoptotic targets in experimental glaucoma and the neuroprotective effects of Ginkgo biloba in retinal ganglion cells Abeir Baltmr MB ChB, FRCS (Glasg) A thesis submitted to University College London for the degree of Doctor of Medicine (Research) 2012 Glaucoma and Retinal Neurodegeneration Research Group Visual Neuroscience Institute of Ophthalmology 1 Declaration I, Abeir Baltmr, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Abeir Baltmr 2 Abstract Ginkgo biloba has been advocated as a neuroprotective agent for several years in glaucoma. In this study, immunohistochemistry was used to identify known potential molecular targets of Ginkgo biloba related to retinal ganglion cell (RGC) apoptosis in experimental glaucoma, including amyloid precursor protein (APP), Aß, cytochrome c, caspase-3 and tumor necrosis factor receptor-1 (TNF-R1). Furthermore, using apoptotic inducers related to mechanisms implicated in glaucoma, namely Dimethyl sulphoxide (DMSO), ultraviolet C (UVC) and Sodium Azide (NaN3), the effects of the terpenoid fraction of Ginkgo biloba (Ginkgolide A, Ginkgolide B and Bilobalide) were investigated separately in cultured retinal ganglion cells (RGC-5). Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and morphological analysis of DMSO treated RGC-5 was performed using Hoechst 33342 stain. Immunohistochemistry showed a strong inverse correlation between Aß and APP in ocular hypertension (OHT) animals, with APP and Aß accumulation peaking at 1 and 12 weeks after intraocular pressure (IOP) elevation respectively. Cytochrome c and TNF-R1 expression peaked at 3 weeks, and active caspase 3 activity at 12 weeks after IOP elevation. -
Ginkgolide B Increases Hydrogen Sulfide and Protects Against Endothelial Dysfunction in Diabetic Rats
4 DISEASE-RELATED CHANGES IN BLOOD VESSELS Croat Med J. 2015;56:4-13 doi: 10.3325/cmj.2015.56.4 Ginkgolide B increases Guo-Guang Wang1*, Qing- Ying Chen2*, Wei Li1, Xiao- hydrogen sulfide and protects Hua Lu1, Xue Zhao1 1Department of Pathophysiology, against endothelial dysfunction Wannan Medical College, Wuhu, in diabetic rats People’s Republic of China 2General Hospital of Jinan Military Command, Jinan, People’s Republic of China *Contributed equally to the study. Aim To evaluate the effect of ginkgolide B treatment on vascular endothelial function in diabetic rats. Methods The study included four groups with 15 male Sprague-Dawley rats: control group; control group treat- ed with ginkgolide B; diabetic group; and diabetic treat- ed with ginkgolide B. The activity of superoxide dismutase (SOD), malondialdehyde content, and nicotinamide ade- nine dinucleotide phosphate (NADPH) oxidase subunits, and glutathione peroxidase 1 (GPX1) protein expression were determined in aortic tissues. Vasoconstriction to phe- nylephrine (PHE) and vasorelaxation to acetylcholine (Ach) and sodium nitroprusside (SNP) were assessed in aortic rings. Nitric oxide (NO) and hydrogen sulfide (H2S) were measured, as well as cystathionine γ lyase (CSE) and cys- tathionine β synthetase (CBS) protein expression, and en- dothelial nitric oxide synthase (eNOS) activity. Results Diabetes significantly impaired PHE-induced va- soconstriction and Ach-induced vasorelaxation (P < 0.001), reduced NO bioavailability and H2S production (P < 0.001), SOD activity, and GPX1 protein expression (P < 0.001), and increased malondialdehyde content and NADPH oxidase subunits, and CSE and CBS protein expression (P < 0.001). Ginkgolide B treatment improved PHE vasoconstriction and Ach vasorelaxation (P < 0.001), restored SOD (P = 0.005) and eNOS (P < 0.001) activities, H2S production (P = 0.044) and decreased malondialdehyde content (P = 0.014). -
Mixed Antagonistic Effects of the Ginkgolides at Recombinant Human R1 GABAC Receptors
Neuropharmacology 63 (2012) 1127e1139 Contents lists available at SciVerse ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Mixed antagonistic effects of the ginkgolides at recombinant human r1 GABAC receptors Shelley H. Huang a, Trevor M. Lewis b, Sarah C.R. Lummis c, Andrew J. Thompson c, Mary Chebib d, Graham A.R. Johnston a, Rujee K. Duke a,* a Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of Sydney, Australia b School of Medical Sciences, University of New South Wales, Australia c Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom d Faculty of Pharmacy, University of Sydney, Australia article info abstract Article history: The diterpene lactones of Ginkgo biloba, ginkgolides A, B and C are antagonists at a range of Cys-loop Received 11 July 2011 receptors. This study examined the effects of the ginkgolides at recombinant human r1 GABAC recep- Received in revised form tors expressed in Xenopus oocytes using two-electrode voltage clamp. The ginkgolides were moderately 18 June 2012 potent antagonists with IC sinthemM range. At 10 mM, 30 mM and 100 mM, the ginkgolides caused Accepted 24 June 2012 50 rightward shifts of GABA doseeresponse curves and reduced maximal GABA responses, characteristic of noncompetitive antagonists, while the potencies showed a clear dependence on GABA concentration, Keywords: indicating apparent competitive antagonism. This suggests that the ginkgolides exert a mixed-type Ginkgolide Bilobalide antagonism at the r1 GABAC receptors. The ginkgolides did not exhibit any obvious use-dependent Mixed-antagonism inhibition. Fitting of the data to a number of kinetic schemes suggests an allosteric inhibition as Use-dependent a possible mechanism of action of the ginkgolides which accounts for their inhibition of the responses GABAr receptor without channel block or use-dependent inhibition. -
Effects of the Putative Antipsychotic Alstonine on Glutamate Uptake in Acute Hippocampal Slices ⇑ Ana P
Neurochemistry International 61 (2012) 1144–1150 Contents lists available at SciVerse ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci Effects of the putative antipsychotic alstonine on glutamate uptake in acute hippocampal slices ⇑ Ana P. Herrmann a,b, , Paula Lunardi b, Luísa Klaus Pilz a, Ana C. Tramontina b, Viviane M. Linck a,b, Christopher O. Okunji c, Carlos A. Gonçalves b, Elaine Elisabetsky a,b a Laboratório de Etnofarmacologia, Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, 90050-170 Porto Alegre, RS, Brazil b Programa de Pós-graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-000 Porto Alegre, RS, Brazil c International Centre for Ethnomedicine and Drug Development (InterCEDD), Nsukka, Enugu State, Nigeria article info abstract Article history: A dysfunctional glutamatergic system is thought to be central to the negative symptoms and cognitive Received 8 March 2012 deficits recognized as determinant to the poor quality of life of people with schizophrenia. Modulating Received in revised form 13 August 2012 glutamate uptake has, thus, been suggested as a novel target for antipsychotics. Alstonine is an indole Accepted 15 August 2012 alkaloid sharing with atypical antipsychotics the profile in animal models relevant to schizophrenia, Available online 25 August 2012 though divergent in its mechanism of action. The aim of this study was to evaluate the effects of alstonine on glutamate uptake. Additionally, the effects on glutathione content and extracellular S100B levels were Keywords: assessed. -
The Role of Kinetic Context in Apparent Biased Agonism at Gpcrs
ARTICLE Received 2 Jul 2015 | Accepted 27 Jan 2016 | Published 24 Feb 2016 DOI: 10.1038/ncomms10842 OPEN The role of kinetic context in apparent biased agonism at GPCRs Carmen Klein Herenbrink1, David A. Sykes2, Prashant Donthamsetti3,4, Meritxell Canals1, Thomas Coudrat1, Jeremy Shonberg5, Peter J. Scammells5, Ben Capuano5, Patrick M. Sexton1, Steven J. Charlton2, Jonathan A. Javitch3,4,6, Arthur Christopoulos1 & J Robert Lane1 Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmaco- logical data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that ‘kinetic context’, as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism. 1 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. 2 Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK. 3 Departments of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. 4 Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. -
Symposium: the Role of 5-HT1AR in Pathophysiology and Treatment Of
Abstracts for oral sessions / European Psychiatry 23 (2008) S1eS80 S61 S51.05 Our transgenic mice showed no overall cognitive deficit. As a ten- Treatment-seeking gamblers and Parkinson’s disease: Case reports dency, inhibitory avoidance retention was impaired in transgenic mice compared to wild-type controls. Both genotypes showed similar O. Simon. Center for Pathological Gambling, Community Psychiatry spatial learning abilities in the Morris water maze and habituated to Services, Department of Adult Psychiatry, University Hospital of the hole-board in a comparable manner. Anterograde amnesia in- Lausanne, Lausanne, Switzerland duced by 8-OH-DPAT was in transgenic mice already apparent in a third of the dose used for wild-type mice. Retrograde amnesia could Pathological gambling (PG) is a rare but well-established behavioural not be triggered. disorders of Parkinson’s disease (PD) patients treated with dopamine agonist. We investigate the chronological relationship between PD Since the transgenic mice show untreated a rather normal be- and diagnosis of PG within treatment-seeking gamblers. haviour, we assume that they possess compensatory mechanisms. However, after activation of the postsynaptic 5-HT1A-receptors Sample and Methods: From 174 consecutively admitted patho- the differences between wild-type and transgenic mice became logical gamblers we identified 4 patients with PD. Standardized med- more clear. Hence, our findings suggest that the cortical and hip- ical records include socio-demographic characteristics, past gaming pocampal 5-HT1A-receptors play rather a modulatory role in behaviours and gambling-treatment modalities as well as the evolu- learning. tion of PD and the pro-dopaminergic medication history. Results: All four patients developed PG after the onset of PD S48.02 treatment. -
(12) United States Patent (10) Patent No.: US 9,687,864 B2 Fulton Et Al
USOO9687864B2 (12) United States Patent (10) Patent No.: US 9,687,864 B2 Fulton et al. (45) Date of Patent: Jun. 27, 2017 (54) SYSTEMAND METHOD FOR ENHANCED 428/25 (2015.01); Y10T 428/31504 (2015.04); ELECTROSTATIC DEPOSITION AND Y10T 428/31507 (2015.04); SURFACE COATINGS (Continued) (58) Field of Classification Search (71) Applicant: Battelle Memorial Institute, USPC .......... 118/620–640; 23.9/690 708; 427/458, Columbus, OH (US) 427/475 4.86 (72) Inventors: John L. Fulton, Richland, WA (US); See application file for complete search history. George S. Deverman, Richland, WA (US); Dean W. Matson, Kennewick, (56) References Cited CA (US); Clement R. Yonker, Kennewick, WA (US); C. Douglas U.S. PATENT DOCUMENTS Taylor, Franklinton, NC (US); James 3,087,860 A 4, 1963 Endicott B. McClain, Raleigh, NC (US); Joseph 3,123,077 A 3, 1964 Alcamo M. Crowley, Cambria, CA (US) (Continued) (73) Assignee: Battelle Memorial Institute, Columbus, OH (US) FOREIGN PATENT DOCUMENTS CA 2589761 12, 2004 (*) Notice: Subject to any disclaimer, the term of this CN 1465410 1, 2004 patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 0 days. (21) Appl. No.: 14/310,960 OTHER PUBLICATIONS Abreu Filho et al., “Influence of metal alloy and the profile of (22) Filed: Jun. 20, 2014 coronary stents in patients with multi-vessel coronary disease.” Clinics 66(6):985-989 (2011). (65) Prior Publication Data (Continued) US 2015/OO40827 A1 Feb. 12, 2015 Related U.S. Application Data Primary Examiner — Yewebdar Tadesse (74) Attorney, Agent, or Firm — Lerner, David, (62) Division of application No. -
Fused Tricyclic Dual Inhibitors of Cdk 4/6 and Flt3
(19) TZZ ¥¥_T (11) EP 2 937 349 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 28.10.2015 Bulletin 2015/44 C07D 471/14 (2006.01) C07D 519/00 (2006.01) A61K 31/519 (2006.01) A61P 35/00 (2006.01) (2006.01) (21) Application number: 15161337.9 A61P 35/02 (22) Date of filing: 21.03.2012 (84) Designated Contracting States: • Keegan, Kathleen S. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Bainbridge Island, WA Washington 98110 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • LI, Zhihong PL PT RO RS SE SI SK SM TR Millbrae, CA California 94030 (US) Designated Extension States: • Lively, Sarah E. BA ME San Carlos, CA California 94070 (US) • McGee, Lawrence R. (30) Priority: 23.03.2011 US 201161466841 P Pacifica, CA California 94044 (US) •Ragains,Mark L. (62) Document number(s) of the earlier application(s) in Fort Worth, TX Texas 76109 (US) accordance with Art. 76 EPC: • Wang, Xianghong 12711738.0 / 2 688 887 Dublin, CA California 94568 (US) • Weidner, Margaret F. (71) Applicant: AMGEN INC. Woodinville, WA Washington 98072 (US) Thousand Oaks, CA 91320-1799 (US) • Zhang, Jian Foster City, CA California 94404 (US) (72) Inventors: • Chen, Xiaoqi (74) Representative: Hoffmann Eitle Palo Alto, CA California 94303 (US) Patent- und Rechtsanwälte PartmbB •Dai,Kang Arabellastraße 30 Albany, CA California 94706 (US) 81925 München (DE) • Duquette, Jason A. Millbrae, CA California 94030 (US) Remarks: • Gribble, Michael W., Jr. This application was filed on 12-05-2015 as a San Francisco, CA California 94110 (US) divisional application to the application mentioned • Huard, Justin N. -
Exploring New Pharmacology and Toxicological Screening and Safety
Zaman et al. BMC Complementary and Alternative Medicine (2015) 15:121 DOI 10.1186/s12906-015-0635-2 RESEARCH ARTICLE Open Access Exploring new pharmacology and toxicological screening and safety evaluation of one widely used formulation of Nidrakar Bati from South Asia region Afria Zaman1, Md Shamsuddin Sultan Khan2*, Lucky Akter1, Sharif Hossain Syeed3, Jakia Akter4, Abdullah Al Mamun5, Md Ershad Alam5, Md Ahsan Habib5 and Md Abdul Jalil5 Abstract Background: Nidrakar Bati (NKB) is an herbal remedy consisted with seven medicinal herbs widely used to cure Somnifacient (sleeping aid) in South Asia as Ayurvedic medicinal system. In the present study, pharmacological and toxicological effects of this medicine was investigated in mice to validate the safety and efficacy of the herb. Methods: Organic solvent extracts NKB were prepared using maceration method. Effect of extracts on the central nervous system was evaluated using hypnotic activity assay. Effect of the extracts on metabolic activity, assessing involvement of thyroid was conducted using hypoxia test. analgesic and anti-inflammatory activities were assessed in mice using acetic acid induced writhing, formalin induced paw edema, xylene induced ear edema assays. Anxiolytic activity was performed using plus maze, climbing out and forced swimming tests. Effect of the extracts on psychopharmacological effect was carried out using locomotor activity tests (open field, Hole-board and Hole-cross tests). Neuropharmacological effect of the extracts was performed using motor coordination (rotarod test). Toxicological potential of the extract was evaluated using gastro-intestinal activity (gastric emptying and gastrointestinal motility tests). Results: The studied formulation reduced the CNS stimulant effects dose independently. In the hypoxia test, only a dose of 100 mg/kg of NKB decreased the survival time.