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Long-term sertraline treatment and depression effects on carotid artery atherosclerosis in premenopausal female primates.
Silverstein-Metzler MG, Justice JN, Appt SE, Groban L, Kitzman DW, Carr JJ, Register TC, Shively CA
(2017) Menopause 24: 1175-1184
MeSH Terms: Animals, Carotid Artery Diseases, Carotid Artery, Common, Depression, Disease Models, Animal, Female, Hot Flashes, Humans, Longitudinal Studies, Macaca fascicularis, Premenopause, Primates, Random Allocation, Risk Factors, Serotonin Uptake Inhibitors, Sertraline
Show Abstract · Added September 11, 2017
OBJECTIVE - Atherosclerosis developed during premenopausal years predicts postmenopausal atherosclerosis burden. Selective serotonin reuptake inhibitor (SSRI) antidepressants, recently approved for hot flushes, have been associated with increased ischemic stroke risk in several observational studies; however, effects on carotid artery atherosclerosis, a strong predictor of future vascular events, are unknown.
METHODS - The effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on atherosclerosis in the carotid artery was assessed in a placebo-controlled, longitudinal, randomized study of premeonopausal depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n = 42). Physiologic and behavioral phenotypes were evaluated at baseline and after 18 months of oral sertraline (20 mg/kg, n = 21) or placebo (n = 21). Carotid artery atherosclerosis was measured post mortem via histomorphometry.
RESULTS - Atherosclerosis extent in the right common carotid artery, on average, was 60% greater in sertraline-treated depressed monkeys compared with all other groups (P = 0.028). The results of linear regression analyses suggested that sertraline and depression effects on atherosclerosis were not mediated by their effects on behavioral and physiological risk factors.
CONCLUSIONS - These findings suggest that chronic SSRI treatment is associated with the progression of carotid artery atherosclerosis, which may increase the risk for future vascular events, particularly in depressed women. The underlying mechanism remains to be determined, but does not appear to be related to SSRI effects on traditional cardiovascular risk factors.
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16 MeSH Terms
Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation.
Felts AS, Rodriguez AL, Blobaum AL, Morrison RD, Bates BS, Thompson Gray A, Rook JM, Tantawy MN, Byers FW, Chang S, Venable DF, Luscombe VB, Tamagnan GD, Niswender CM, Daniels JS, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
(2017) J Med Chem 60: 5072-5085
MeSH Terms: Allosteric Regulation, Aminopyridines, Animals, Chemistry Techniques, Synthetic, Drug Evaluation, Preclinical, HEK293 Cells, High-Throughput Screening Assays, Humans, Macaca fascicularis, Male, Mice, Inbred Strains, Picolinic Acids, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Tissue Distribution
Show Abstract · Added March 21, 2018
Preclinical evidence in support of the potential utility of mGlu NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu versus the other mGlu receptors, and binding studies established a K value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.
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16 MeSH Terms
Therapeutic treatment of Marburg and Ravn virus infection in nonhuman primates with a human monoclonal antibody.
Mire CE, Geisbert JB, Borisevich V, Fenton KA, Agans KN, Flyak AI, Deer DJ, Steinkellner H, Bohorov O, Bohorova N, Goodman C, Hiatt A, Kim DH, Pauly MH, Velasco J, Whaley KJ, Crowe JE, Zeitlin L, Geisbert TW
(2017) Sci Transl Med 9:
MeSH Terms: Animals, Antibodies, Monoclonal, Cross Protection, Filoviridae, Filoviridae Infections, Guinea Pigs, Humans, Macaca fascicularis, Macaca mulatta, Marburg Virus Disease, Marburgvirus, Pilot Projects
Show Abstract · Added April 13, 2017
As observed during the 2013-2016 Ebola virus disease epidemic, containment of filovirus outbreaks is challenging and made more difficult by the lack of approved vaccine or therapeutic options. Marburg and Ravn viruses are highly virulent and cause severe and frequently lethal disease in humans. Monoclonal antibodies (mAbs) are a platform technology in wide use for autoimmune and oncology indications. Previously, we described human mAbs that can protect mice from lethal challenge with Marburg virus. We demonstrate that one of these mAbs, MR191-N, can confer a survival benefit of up to 100% to Marburg or Ravn virus-infected rhesus macaques when treatment is initiated up to 5 days post-inoculation. These findings extend the small but growing body of evidence that mAbs can impart therapeutic benefit during advanced stages of disease with highly virulent viruses and could be useful in epidemic settings.
Copyright © 2017, American Association for the Advancement of Science.
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12 MeSH Terms
Sertraline inhibits increases in body fat and carbohydrate dysregulation in adult female cynomolgus monkeys.
Silverstein-Metzler MG, Shively CA, Clarkson TB, Appt SE, Carr JJ, Kritchevsky SB, Jones SR, Register TC
(2016) Psychoneuroendocrinology 68: 29-38
MeSH Terms: Adipose Tissue, Animals, Antidepressive Agents, Body Composition, Body Weight, Carbohydrate Metabolism, Depression, Drug Administration Schedule, Female, Insulin, Longitudinal Studies, Macaca fascicularis, Models, Animal, Random Allocation, Serotonin Uptake Inhibitors, Sertraline
Show Abstract · Added September 29, 2016
Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed for depression and other disorders. SSRIs have become one of the most commonly used drugs in the United States, particularly by women. Acute effects on body composition and carbohydrate metabolism have been reported, but little is known regarding the effects of chronic SSRI use. We evaluated the effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on body weight and composition, fat distribution, carbohydrate metabolism, as well as activity, in adult female depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n=42) using a placebo-controlled, longitudinal, randomized study design. Phenotypes were evaluated prior to and after 18 months of oral sertraline (20mg/kg) or placebo. Over the 18 month treatment period, the placebo group experienced increases in body weight, body fat (visceral and subcutaneous) fasting insulin concentrations, and homeostasis model assessment of insulin resistance scores (HOMA-IR). Sertraline treatment prevented increases in body weight, fat, insulin, and HOMA-IR (all p<0.05), without significantly altering activity levels. Sertraline treatment altered adiponectin in an unusual way - reducing circulating adiponectin in depressed monkeys without affecting fat mass or body weight. Deleterious effects on adiponectin, a potentially insulin-sensitizing and atheroprotective protein, may result in adverse effects on cardiovascular health despite otherwise beneficial effects on body composition and carbohydrate metabolism.
Copyright © 2016. Published by Elsevier Ltd.
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16 MeSH Terms
Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex.
Kolumam G, Chen MZ, Tong R, Zavala-Solorio J, Kates L, van Bruggen N, Ross J, Wyatt SK, Gandham VD, Carano RA, Dunshee DR, Wu AL, Haley B, Anderson K, Warming S, Rairdan XY, Lewin-Koh N, Zhang Y, Gutierrez J, Baruch A, Gelzleichter TR, Stevens D, Rajan S, Bainbridge TW, Vernes JM, Meng YG, Ziai J, Soriano RH, Brauer MJ, Chen Y, Stawicki S, Kim HS, Comps-Agrar L, Luis E, Spiess C, Wu Y, Ernst JA, McGuinness OP, Peterson AS, Sonoda J
(2015) EBioMedicine 2: 730-43
MeSH Terms: Adiponectin, Adipose Tissue, Brown, Animals, Antibodies, Bispecific, Cell Line, Energy Metabolism, Fibroblast Growth Factors, HEK293 Cells, Humans, Insulin, Macaca fascicularis, Male, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Obese, Protein Binding, Receptor, Fibroblast Growth Factor, Type 1, Thermogenesis, Weight Loss
Show Abstract · Added September 10, 2015
Dissipating excess calories as heat through therapeutic stimulation of brown adipose tissues (BAT) has been proposed as a potential treatment for obesity-linked disorders. Here, we describe the generation of a humanized effector-less bispecific antibody that activates fibroblast growth factor receptor (FGFR) 1/βKlotho complex, a common receptor for FGF21 and FGF19. Using this molecule, we show that antibody-mediated activation of FGFR1/βKlotho complex in mice induces sustained energy expenditure in BAT, browning of white adipose tissue, weight loss, and improvements in obesity-associated metabolic derangements including insulin resistance, hyperglycemia, dyslipidemia and hepatosteatosis. In mice and cynomolgus monkeys, FGFR1/βKlotho activation increased serum high-molecular-weight adiponectin, which appears to contribute over time by enhancing the amplitude of the metabolic benefits. At the same time, insulin sensitization by FGFR1/βKlotho activation occurs even before the onset of weight loss in a manner that is independent of adiponectin. Together, selective activation of FGFR1/βKlotho complex with a long acting therapeutic antibody represents an attractive approach for the treatment of type 2 diabetes and other obesity-linked disorders through enhanced energy expenditure, insulin sensitization and induction of high-molecular-weight adiponectin.
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20 MeSH Terms
Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents.
Bubser M, Bridges TM, Dencker D, Gould RW, Grannan M, Noetzel MJ, Lamsal A, Niswender CM, Daniels JS, Poslusney MS, Melancon BJ, Tarr JC, Byers FW, Wess J, Duggan ME, Dunlop J, Wood MW, Brandon NJ, Wood MR, Lindsley CW, Conn PJ, Jones CK
(2014) ACS Chem Neurosci 5: 920-42
MeSH Terms: Amphetamines, Animals, Association Learning, Brain, Cell Line, Central Nervous System Stimulants, Cholinergic Agents, Cricetulus, Dizocilpine Maleate, Dogs, Dose-Response Relationship, Drug, Excitatory Amino Acid Antagonists, Humans, Macaca fascicularis, Male, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Psychotropic Drugs, Pyridazines, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M4, Thiophenes
Show Abstract · Added February 19, 2015
Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders.
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24 MeSH Terms
Adipose tissue density, a novel biomarker predicting mortality risk in older adults.
Murphy RA, Register TC, Shively CA, Carr JJ, Ge Y, Heilbrun ME, Cummings SR, Koster A, Nevitt MC, Satterfield S, Tylvasky FA, Strotmeyer ES, Newman AB, Simonsick EM, Scherzinger A, Goodpaster BH, Launer LJ, Eiriksdottir G, Sigurdsson S, Sigurdsson G, Gudnason V, Lang TF, Kritchevsky SB, Harris TB
(2014) J Gerontol A Biol Sci Med Sci 69: 109-17
MeSH Terms: Absorptiometry, Photon, Adiponectin, Adipose Tissue, Aged, Aged, 80 and over, Aging, Animals, Biomarkers, Body Mass Index, Female, Follow-Up Studies, Humans, Leptin, Macaca fascicularis, Male, Obesity, Prognosis, Prospective Studies, Risk Factors, Survival Rate
Show Abstract · Added February 28, 2014
BACKGROUND - Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics.
METHODS - VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4-13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics.
RESULTS - Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36-2.80; Health ABC) and 1.88 (1.31-2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35-2.28; Health ABC) and 1.56 (1.15-2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12-2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21-2.07), and AGES-Reykjavik, 1.43 (1.07-1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs.
CONCLUSION - VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.
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20 MeSH Terms
Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates.
Crosby JR, Marzec U, Revenko AS, Zhao C, Gao D, Matafonov A, Gailani D, MacLeod AR, Tucker EI, Gruber A, Hanson SR, Monia BP
(2013) Arterioscler Thromb Vasc Biol 33: 1670-8
MeSH Terms: Animals, Antibodies, Monoclonal, Arteriovenous Shunt, Surgical, Bleeding Time, Blood Coagulation, Collagen, Disease Models, Animal, Dose-Response Relationship, Drug, Down-Regulation, Factor XI, Fibrinolytic Agents, Hemorrhage, Macaca fascicularis, Oligonucleotides, Antisense, Papio, Thrombin, Thrombosis, Time Factors
Show Abstract · Added May 19, 2014
OBJECTIVE - During coagulation, factor IX (FIX) is activated by 2 distinct mechanisms mediated by the active proteases of either FVIIa or FXIa. Both coagulation factors may contribute to thrombosis; FXI, however, plays only a limited role in the arrest of bleeding. Therefore, therapeutic targeting of FXI may produce an antithrombotic effect with relatively low hemostatic risk.
APPROACH AND RESULTS - We have reported that reducing FXI levels with FXI antisense oligonucleotides produces antithrombotic activity in mice, and that administration of FXI antisense oligonucleotides to primates decreases circulating FXI levels and activity in a dose-dependent and time-dependent manner. Here, we evaluated the relationship between FXI plasma levels and thrombogenicity in an established baboon model of thrombosis and hemostasis. In previous studies with this model, antibody-induced inhibition of FXI produced potent antithrombotic effects. In the present article, antisense oligonucleotides-mediated reduction of FXI plasma levels by ≥ 50% resulted in a demonstrable and sustained antithrombotic effect without an increased risk of bleeding.
CONCLUSIONS - These results indicate that reducing FXI levels using antisense oligonucleotides is a promising alternative to direct FXI inhibition, and that targeting FXI may be potentially safer than conventional antithrombotic therapies that can markedly impair primary hemostasis.
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18 MeSH Terms
Differential expression of vesicular glutamate transporters 1 and 2 may identify distinct modes of glutamatergic transmission in the macaque visual system.
Balaram P, Hackett TA, Kaas JH
(2013) J Chem Neuroanat 50-51: 21-38
MeSH Terms: Animals, Blotting, Western, Glutamic Acid, Immunohistochemistry, In Situ Hybridization, Macaca fascicularis, Synaptic Transmission, Vesicular Glutamate Transport Protein 1, Vesicular Glutamate Transport Protein 2, Visual Cortex, Visual Pathways
Show Abstract · Added April 6, 2017
Glutamate is the primary neurotransmitter utilized by the mammalian visual system for excitatory neurotransmission. The sequestration of glutamate into synaptic vesicles, and the subsequent transport of filled vesicles to the presynaptic terminal membrane, is regulated by a family of proteins known as vesicular glutamate transporters (VGLUTs). Two VGLUT proteins, VGLUT1 and VGLUT2, characterize distinct sets of glutamatergic projections between visual structures in rodents and prosimian primates, yet little is known about their distributions in the visual system of anthropoid primates. We have examined the mRNA and protein expression patterns of VGLUT1 and VGLUT2 in the visual system of macaque monkeys, an Old World anthropoid primate, in order to determine their relative distributions in the superior colliculus, lateral geniculate nucleus, pulvinar complex, V1 and V2. Distinct expression patterns for both VGLUT1 and VGLUT2 identified architectonic boundaries in all structures, as well as anatomical subdivisions of the superior colliculus, pulvinar complex, and V1. These results suggest that VGLUT1 and VGLUT2 clearly identify regions of glutamatergic input in visual structures, and may identify common architectonic features of visual areas and nuclei across the primate radiation. Additionally, we find that VGLUT1 and VGLUT2 characterize distinct subsets of glutamatergic projections in the macaque visual system; VGLUT2 predominates in driving or feedforward projections from lower order to higher order visual structures while VGLUT1 predominates in modulatory or feedback projections from higher order to lower order visual structures. The distribution of these two proteins suggests that VGLUT1 and VGLUT2 may identify class 1 and class 2 type glutamatergic projections within the primate visual system (Sherman and Guillery, 2006).
Copyright © 2013 Elsevier B.V. All rights reserved.
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11 MeSH Terms
The role of aldehyde oxidase and xanthine oxidase in the biotransformation of a novel negative allosteric modulator of metabotropic glutamate receptor subtype 5.
Morrison RD, Blobaum AL, Byers FW, Santomango TS, Bridges TM, Stec D, Brewer KA, Sanchez-Ponce R, Corlew MM, Rush R, Felts AS, Manka J, Bates BS, Venable DF, Rodriguez AL, Jones CK, Niswender CM, Conn PJ, Lindsley CW, Emmitte KA, Daniels JS
(2012) Drug Metab Dispos 40: 1834-45
MeSH Terms: Aldehyde Oxidase, Allopurinol, Animals, Benzamides, Biotransformation, Chromatography, Liquid, Enzyme Inhibitors, Excitatory Amino Acid Antagonists, Hepatocytes, Humans, Hydroxylation, Injections, Intravenous, Liver, Macaca fascicularis, Magnetic Resonance Spectroscopy, Male, Metabolic Clearance Rate, Microsomes, Liver, Models, Biological, Molecular Structure, Oxygen Isotopes, Raloxifene Hydrochloride, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Species Specificity, Tandem Mass Spectrometry, Thiazoles, Xanthine Oxidase
Show Abstract · Added March 7, 2014
Negative allosteric modulation (NAM) of metabotropic glutamate receptor subtype 5 (mGlu₅) represents a therapeutic strategy for the treatment of childhood developmental disorders, such as fragile X syndrome and autism. VU0409106 emerged as a lead compound within a biaryl ether series, displaying potent and selective inhibition of mGlu₅. Despite its high clearance and short half-life, VU0409106 demonstrated efficacy in rodent models of anxiety after extravascular administration. However, lack of a consistent correlation in rat between in vitro hepatic clearance and in vivo plasma clearance for the biaryl ether series prompted an investigation into the biotransformation of VU0409106 using hepatic subcellular fractions. An in vitro appraisal in rat, monkey, and human liver S9 fractions indicated that the principal pathway was NADPH-independent oxidation to metabolite M1 (+16 Da). Both raloxifene (aldehyde oxidase inhibitor) and allopurinol (xanthine oxidase inhibitor) attenuated the formation of M1, thus implicating the contribution of both molybdenum hydroxylases in the biotransformation of VU0409106. The use of ¹⁸O-labeled water in the S9 experiments confirmed the hydroxylase mechanism proposed, because ¹⁸O was incorporated into M1 (+18 Da) as well as in a secondary metabolite (M2; +36 Da), the formation of which was exclusively xanthine oxidase-mediated. This unusual dual and sequential hydroxylase metabolism was confirmed in liver S9 and hepatocytes of multiple species and correlated with in vivo data because M1 and M2 were the principal metabolites detected in rats administered VU0409106. An in vitro-in vivo correlation of predicted hepatic and plasma clearance was subsequently established for VU0409106 in rats and nonhuman primates.
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30 MeSH Terms