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Schizophrenia histamine

Adam J Prus, Laura E Wise, Alan L Pehrson, Scott D Philibin, Benny Bang-Andersen, Jørn Arnt, Joseph H Porter
The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects...
October 1, 2016: Brain Research
Fang Fang, Hongwei Sun, Zuowei Wang, Ming Ren, Joseph R Calabrese, Keming Gao
Somnolence is a common side effect of antipsychotics. To assess the incidence of this side effect, we performed a MEDLINE search for randomized, double-blinded, placebo- or active-controlled studies of adult patients treated with antipsychotics for schizophrenia, mania, bipolar depression, or bipolar disorder. We extracted rates of somnolence from original publications and pooled them based on the dose of each antipsychotic in the same psychiatric condition, then estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic relative to placebo or an active comparator in the same psychiatric condition...
September 2016: CNS Drugs
Aya Goto, Akihiro Mouri, Tomoko Nagai, Akira Yoshimi, Mako Ukigai, Tomomi Tsubai, Hirotake Hida, Norio Ozaki, Yukihiro Noda
Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells...
September 1, 2016: Toxicology and Applied Pharmacology
Bassem Sadek, Ali Saad, Adel Sadeq, Fakhreya Jalal, Holger Stark
The potential contributions of the brain histaminergic system in neurodegenerative diseases, and the possiblity of histamine-targeting treatments is attracting considerable interests. The histamine H3 receptor (H3R) is expressed mainly in the central nervous system, and is, consequently, an attractive pharmacological target. Although recently described clinical trials have been disappointing in attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCH), numerous H3R antagonists, including pitolisant, demonstrate potential in the treatment of narcolepsy, excessive daytime sleepiness associated with cognitive impairment, epilepsy, and Alzheimer's disease (AD)...
October 1, 2016: Behavioural Brain Research
Alexandre V Ivachtchenko, Yan Lavrovsky, Ilya Okun
Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101...
May 25, 2016: Journal of Alzheimer's Disease: JAD
P De Deurwaerdère
Cariprazine (RGH-188, MP-214, Vraylar[TM]) is a new dopamine receptor ligand developed for the treatment of several neuropsychiatric diseases including schizophrenia and bipolar disorders. Cariprazine displays higher affinity at dopamine D3 receptors and a similar affinity at D2 and 5-HT2B receptors. At variance with some atypical antipsychotics, its affinity at 5-HT1A, 5-HT2A and histamine H1 receptors is modest compared with its three main targets. Cariprazine could correspond to a biased agonist at dopamine receptors, displaying either antagonist or partial agonist properties depending on the signaling pathways linked to D2/D3 receptors...
February 2016: Drugs of Today
Yue Pei, Aman Asif-Malik, Juan J Canales
Biogenic amines are a collection of endogenous molecules that play pivotal roles as neurotransmitters and hormones. In addition to the "classical" biogenic amines resulting from decarboxylation of aromatic acids, including dopamine (DA), norepinephrine, epinephrine, serotonin (5-HT), and histamine, other biogenic amines, present at much lower concentrations in the central nervous system (CNS), and hence referred to as "trace" amines (TAs), are now recognized to play significant neurophysiological and behavioral functions...
2016: Frontiers in Neuroscience
Danish Mahmood, Mohd Akhtar, Kausar Jahan, Dipanjan Goswami
BACKGROUND: Animal models based on N-methyl-d-aspartate receptor blockade have been extensively used for schizophrenia. Ketamine and MK-801 produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia, which led to the use of PCP (phencyclidine)- and MK-801 (dizocilpine)-treated animals as models for schizophrenia. METHODS: The study investigated the effect of subchronic dosing (once daily, 7 days) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i...
September 1, 2016: Journal of Basic and Clinical Physiology and Pharmacology
Nir Barak, Yaffa Beck, Joseph H Albeck
Patients with schizophrenia experience higher rates of obesity and related morbidity and mortality than the general population does. Given preclinical studies revealing the role of histamine H1 receptor in human eating behavior, and the potential of olanzapine to block with this system, we hypothesized that histamine H1 receptor agonists may be beneficial in reducing antipsychotic-associated weight gain. In the present study, 36 patients with a diagnosis of schizophrenia or schizoaffective disorder and treated with olanzapine were randomized to betahistine (48 mg/d) or matching placebo for 16 weeks...
June 2016: Journal of Clinical Psychopharmacology
Nir Barak, Yaffa Beck, Joseph H Albeck
Olanzapine's efficacy in schizophrenia is attributed to antagonism of dopamine and serotonin receptors. Olanzapine is also a potent histamine-H1 antagonist that results in weight gain and somnolence. Betahistine is a centrally acting histamine-H1 agonist, and therefore may reduce olanzapine's effect on histamine receptors in the brain. Olanzapine's high affinity for the histamine-H1 receptor warrants the use of high doses of betahistine. Forty-eight healthy women were recruited and randomized to receive either betahistine 144 mg/day or matching placebo for 4 weeks...
March 2016: Journal of Psychopharmacology
Mark J Hunt, Maciej Olszewski, Joanna Piasecka, Miles A Whittington, Stefan Kasicki
RATIONALE: Abnormal oscillatory activity associated with N-methyl-D-aspartate (NMDA) receptor hypofunction is widely considered to contribute to the symptoms of schizophrenia. OBJECTIVE: This study aims to characterise the changes produced by NMDA receptor antagonists and antipsychotics on accumbal high-frequency oscillations (HFO; 130-180 Hz) in mice. METHODS: Local field potentials were recorded from the nucleus accumbens of freely moving mice...
December 2015: Psychopharmacology
Maximiliano Rapanelli, Christopher Pittenger
The potential contributions of dysregulation of the brain's histaminergic modulatory system to neuropsychiatric disease, and the potential of histamine-targeting medications as therapeutic agents, are gradually coming into focus. The H3R receptor, which is expressed primarily in the central nervous system, is a promising pharmacotherapeutic target. Recent evidence for a contribution of histamine dysregulation to Tourette syndrome and tic disorders is particularly strong; although specific mutations in histamine-associated genes are rare, they have led to informative studies in animal models that may pave the way for therapeutic advances...
July 2016: Neuropharmacology
Bart A Ellenbroek, Bibinaz Ghiabi
In spite of almost 60 years of experience with the pharmacological treatment of schizophrenia, there is still a large unmet medical need for better control of especially the negative and cognitive symptoms of schizophrenia. One potential new avenue is the selective blockade of histamine H3 receptors (H3R). Based on a large basis of preclinical data, H3R antagonists or inverse agonists have been suggested to improve cognition in a variety of neurological and psychiatric indications. The aim of the present paper is to review the potential usefulness of H3R antagonists for the treatment of schizophrenia...
2015: Current Pharmaceutical Design
Xinglong Yang, Chuanxin Liu, Jinxiang Zhang, Hongying Han, Xiuyan Wang, Zhoulin Liu, Yanming Xu
Parkinson's disease (PD) and schizophrenia (SCZ) are frequent central nervous disorders that have unclear etiologies but that show similarities in their pathogenesis. Since elevated histamine levels in the brain have been associated with PD and SCZ, we wanted to explore whether the Thr105Ile substitution in the histamine N-methyltransferase gene (HNMT-Thr105Ile), which impairs histamine degradation, is associated with either disease. We used the ligase detection reaction to genotype a case-control cohort of Han Chinese patients with PD or SCZ and healthy controls at the HNMT-Thr105Ile locus...
2015: PloS One
L Fredrik Jarskog, Martin T Lowy, Richard A Grove, Richard S E Keefe, Joseph P Horrigan, M Patricia Ball, Alan Breier, Robert W Buchanan, Cameron S Carter, John G Csernansky, Donald C Goff, Michael F Green, Joshua T Kantrowitz, Matcheri S Keshavan, Marc Laurelle, Jeffrey A Lieberman, Stephen R Marder, Paul Maruff, Robert P McMahon, Larry J Seidman, Margaret A Peykamian
This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0...
May 2015: Schizophrenia Research
F J B Mendonça Júnior, L Scotti, H Ishiki, S P S Botelho, M S Da Silva, M T Scotti
Benzodiazepines (BZ or BZD) are a class of gabaminergic psychoactive chemicals used in hypnotics, sedation, in the treatment of anxiety, and in other CNS disorders. These drugs include alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), and others. There are two distinct types of pharmacological binding sites for benzodiazepines in the brain (BZ1 and BZ2), these sites are on GABA-A receptors, and are classified as short, intermediate, or long-acting. From the thienobenzodiazepine class (TBZ), Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) (Zyprexa) was used as an example to demonstrate the antagonism of this class of compounds for multiples receptors including: dopamine D1-D5, α-adrenoreceptor, histamine H1, muscarinic M1-M5 and 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT6 receptors...
2015: Mini Reviews in Medicinal Chemistry
David Y Lewis, Sue Champion, David Wyper, Deborah Dewar, Sally Pimlott
Histamine H3 receptor therapeutics have been proposed for several diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease and obesity. We set out to evaluate the novel compound, [125I]WYE-230949, as a potential radionuclide imaging agent for the histamine H3 receptor in brain. [125I]WYE-230949 had a high in vitro affinity for the rat histamine H3 receptor (Kd of 6.9 nM). The regional distribution of [125I]WYE-230949 binding sites in rat brain, demonstrated by in vitro autoradiography, was consistent with the known distribution of the histamine H3 receptor...
2014: PloS One
Diego Baronio, Taylor Gonchoroski, Kamila Castro, Geancarlo Zanatta, Carmem Gottfried, Rudimar Riesgo
Histamine and its receptors were first described as part of immune and gastrointestinal systems, but their presence in the central nervous system and importance in behavior are gaining more attention. The histaminergic system modulates different processes including wakefulness, feeding, and learning and memory consolidation. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the rhodopsin-like family of G protein-coupled receptors, present constitutive activity, and are subjected to inverse agonist action...
2014: Annals of General Psychiatry
Christoph U Correll
A variety of antipsychotic medications exist for treating patients with schizophrenia. Knowledge of pharmacokinetics (the body's effect on the drug) and pharmacodynamics (the drug's effect on the body) can help clinicians select antipsychotics and make timely dose adjustments to improve patient outcomes. Currently, the only known effective mechanism to reduce positive psychotic symptoms is dopamine D2 blockade. However, several relevant dopamine pathways exist, and increasingly sophisticated insight into the role of subsections of the striatum has helped link dopamine D2 blockade in specific pathways to the beneficial and adverse effects of antipsychotics, including extrapyramidal side effects (EPS) and secondary negative or cognitive effects...
September 2014: Journal of Clinical Psychiatry
Luca Lipani, Dalibor Odadzic, Lilia Weizel, Johannes-Stephan Schwed, Bassem Sadek, Holger Stark
The histamine H3 receptor (H3R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H3R selective antagonists/inverse agonists, e...
October 30, 2014: European Journal of Medicinal Chemistry
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