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Both preclinical evidence and clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, the decline of which is associated with conditions such as Alzheimer's disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in an attempt to avoid the rapid desensitization properties associated with the α7nAChR after orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on the pharmacologic characterization of the novel compound RO5126946 (5-chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide), which allosterically modulates α7nAChR activity. RO5126946 increased acetylcholine-evoked peak current and delayed current decay but did not affect the recovery of α7nAChRs from desensitization. In addition, RO5126946's effects were absent when nicotine-evoked currents were completely blocked by coapplication of the α7nAChR-selective antagonist methyl-lycaconitine. RO5126946 enhanced α7nAChR synaptic transmission and positively modulated GABAergic responses. The absence of RO5126946 effects at human α4ß2nAChR and 5-hydroxytryptamine 3 receptors, among others, indicated selectivity for α7nAChRs. In vivo, RO5126946 is orally bioavailable and brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rats. In addition, procognitive effects of RO5126946 were investigated in the presence of nicotine to address potential pharmacologic interactions on behavior. RO5126946 potentiated nicotine's effects on fear memory when both compounds were administered at subthreshold doses and did not interfere with procognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel α7nAChR PAM with cognitive-enhancing properties.
Assuntos
Benzamidas/farmacologia , Sulfonamidas/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Regulação Alostérica , Animais , Células Cultivadas , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Nicotina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/fisiologia , Receptores de Glutamato/fisiologiaRESUMO
BACKGROUND: Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested. METHODS: In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in BPS in mice. RESULTS: Chronic treatment with RO6871135, 7.5 mg/kg increased AHN and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of AHN by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMK2a, CaMK2b, MAP2K6, and GSK3b. An analog compound also demonstrated high affinity for CDK8, CaMK2a, and GSK3b. CONCLUSIONS: These studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS, and points to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.
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In order to predict the effects of climate change on polar ecosystems, disentangling mechanisms of nutrient transfer in food webs is crucial. We investigated sources of nutrients in tundra lakes, tracing their transfer through the food web and relating the observed patterns to runoff, snow coverage, and the presence of migratory geese in lake catchments. C and N content (elemental and isotopic) of several food web components including Lepidurus arcticus (Notostraca, at the top of the lake food webs) in 18 shallow Arctic lakes was compared. Terrestrial productivity and geese abundance were key biotic factors that interacted with abiotic variables (snow coverage, lake and catchment size) in determining the amount and origin of nutrient inputs, affecting the trophic interactions among aquatic species, food chain length and nutrient flow in Arctic lake food webs. Decreasing snow coverage, increasing abundance and expansion of the geese's range are expected across the Arctic due to climate warming. By relating nutrient inputs and food web structure to snow coverage, vegetation and geese, this study contributes to our mechanistic understanding of the cascade effects of climate change in tundra ecosystems, and may help predict the response of lakes to changes in nutrient inputs at lower latitudes.
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Achondroplasia is the most common form of short-limb dwarfism. In this disorder, endochondral ossification is impaired due to gain-of-function mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene. In addition to short limbs, cranial base bones are also affected leading to shortening of the skull base and to serious neurological complications associated with foramen magnum stenosis. These complications are thought to be due to the delay or premature arrest of skull base growth, caused by an accelerated ossification of the sphenooccipital (SOS) and the intraoccipital (IOS) synchondroses. Skull synchondroses consist of two opposite growth plates sharing a common reserve zone of chondrocytes. In this study, we first characterized the skull base synchondroses ossification in a mouse model of achondroplasia carrying the human G380R mutation (Fgfr3 ach/+ ). We then addressed whether Recifercept, a soluble FGFR3, could prevent premature closure of these synchondroses. Postnatal radiological observations revealed the presence of bony bridge structures in one or more synchondroses in Fgfr3 ach/+ mice as early as postnatal day 3 in the most severe cases. The presence of early ossification correlated with the severity of the disease as it was associated with an arrest of the cranial base bone growth. Histological analyses indicated changes in the synchondroses structure and matrix proteoglycan contents confirming a process of ossification. Treatment of Fgfr3 ach/+ mice with Recifercept compared with vehicle prevented premature synchondrosis ossification and the transition to bone, resulting in improved skull shape and cranium ratio. Given the impact of Recifercept on synchondrosis inactivation, it is possible that it could prevent one of the most severe complication of achondroplasia if used early enough during bone development. These data support the clinical development of Recifercept for achondroplasia, and suggests that early treatment may be required to best address impaired endochondral bone growth. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Neuronal nicotinic α7 acetylcholine receptors (α7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at α7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) binds potently to the human α7nAChR (K(i) = 6 nM), in which it acts as a partial agonist (63-69% of acetylcholine) as assessed by whole-cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human α7nAChRs with an EC(50) of 0.8 µM (oocytes) and 7.7 µM (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC(50) = 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: ≤0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent α7nAChR partial agonist that improves cognitive performance and sensorimotor gating.
Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Cognição/fisiologia , Agonismo Parcial de Drogas , Indazóis/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/fisiologia , Filtro Sensorial/fisiologia , Animais , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Linhagem Celular Tumoral , Cognição/efeitos dos fármacos , Feminino , Humanos , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Long-Evans , Ratos Sprague-Dawley , Ratos Wistar , Filtro Sensorial/efeitos dos fármacos , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.
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Proliferação de Células/efeitos da radiação , Giro Denteado/fisiologia , Aprendizagem em Labirinto/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Antidepressivos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento Animal/efeitos da radiação , Bromodesoxiuridina , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Divisão Celular/efeitos da radiação , Giro Denteado/efeitos dos fármacos , Giro Denteado/efeitos da radiação , Ambiente Controlado , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Comportamento Alimentar/efeitos da radiação , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/fisiologia , Habituação Psicofisiológica/efeitos da radiação , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos da radiação , Transtornos da Memória/fisiopatologia , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/efeitos da radiação , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Células-Tronco/efeitos da radiação , Raios XRESUMO
Achondroplasia is a rare genetic disorder caused by mutations in the Fibroblast Growth Factor receptor 3 (FGFR3). These mutations lead to aberrant increase of inhibitory signaling in proliferating chondrocytes at the growth plate. Recifercept is a potential treatment for this disease using a decoy approach to sequester FGFR3 ligands subsequently normalizing activation of the mutated FGFR3 receptor. Recifercept binds to FGF isoforms in vitro and in cellular model systems and reduces FGFR3 signaling. In addition, in a transgenic mouse model of achondroplasia, Recifercept restores reduced body weight and long bone growth in these mice. These data suggest that Recifercept treatment could lead to clinical benefits in children treated with this molecule.
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Acondroplasia/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/metabolismo , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/administração & dosagem , Acondroplasia/genética , Acondroplasia/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Ligação Proteica/efeitos dos fármacos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
New neurons are generated in the adult hippocampus of many species including rodents, monkeys, and humans. Conditions associated with major depression, such as social stress, suppress hippocampal neurogenesis in rodents and primates. In contrast, all classes of antidepressants stimulate neuronal generation, and the behavioral effects of these medications are abolished when neurogenesis is blocked. These findings generated the hypothesis that induction of neurogenesis is a necessary component in the mechanism of action of antidepressant treatments. To date, the effects of antidepressants on newborn neurons have been reported only in rodents and tree shrews. This study examines whether neurogenesis is increased in nonhuman primates after antidepressant treatment. Adult monkeys received repeated electroconvulsive shock (ECS), which is the animal analog of electroconvulsive therapy (ECT), the most effective short-term antidepressant. Compared with control conditions, ECS robustly increased precursor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus in the monkey hippocampus. A majority of these precursors differentiated into neurons or endothelial cells, while a few matured into glial cells. The ECS-mediated induction of cell proliferation and neurogenesis was accompanied by increased immunoreactivity for the neuroprotective gene product BCL2 (B cell chronic lymphocytic lymphoma 2) in the SGZ. The ECS interventions were not accompanied by increased hippocampal cell death or injury. This study demonstrates that ECS is capable of inducing neurogenesis in the nonhuman primate hippocampus and supports the possibility that antidepressant interventions produce similar alterations in the human brain.
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Diferenciação Celular/fisiologia , Depressão/patologia , Depressão/terapia , Eletrochoque/métodos , Hipocampo/citologia , Neurônios/citologia , Animais , Hipocampo/fisiologia , Macaca radiata , Masculino , Neurônios/fisiologiaRESUMO
Elevation of intracellular cyclic adenosine monophosphate (cAMP) concentrations and subsequent regulation of downstream target gene expression through phosphorylation of cAMP-responsive element binding protein (CREB) is hypothesized to underlie the mechanism(s) of long-term memory (LTM) formation. The phosphodiesterase 4 (PDE4) enzyme family is believed to play a key role in LTM by regulating cAMP levels. Thus far, four PDE4 isoforms have been identified (PDE4A, B, C and D); however, the requisite involvement of each of these isoforms in mediating LTM has yet to be elucidated. In the present study, genetic knockout mice were used to investigate the involvement of the PDE4D isoform in both in vitro and in vivo models of learning and memory. Hippocampal synaptic transmission measured electrophysiologically in CA1 slice preparations was similar between wild-type and PDE4D (-/-) mice yet, relative to wild-type controls, knockout mice displayed enhanced early long-term potentiation (LTP) following multiple induction protocols. Interestingly, the PDE4D (-/-) animals exhibited significant behavioral deficits in associative learning using a conditioned fear paradigm as compared with control littermates. The impairment in fear conditioning observed in the PDE4D (-/-) mice could not be attributed to differences in acquisition of the task, alterations in locomotor activity or effects on shock sensitivity. Overall, the in vitro and in vivo alterations in synaptic plasticity observed in the PDE4D (-/-) mice may be explained by adaptive responses occurring throughout development, and suggest that the PDE4D isoform may be an important mediator of LTM formation.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Isoenzimas/metabolismo , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Animais , Comportamento Animal/fisiologia , Condicionamento Clássico/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Eletrofisiologia , Medo/fisiologia , Isoenzimas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
OBJECTIVE: The objectives of this paper are to develop and test the ability of a wearable physiological sensors system, based on ECG, EDA, and EEG, to capture human stress and to assess whether the detected changes in physiological signals correlate with changes in salivary cortisol level, which is a reliable, objective biomarker of stress. METHODS: 15 healthy participants, eight males and seven females, mean age 40.8 ± 9.5 years, wore a set of three commercial sensors to record physiological signals during the Maastricht Acute Stress Test, an experimental protocol known to elicit robust physical and mental stress in humans. Salivary samples were collected throughout the different phases of the test. Statistical analysis was performed using a support vector machine (SVM) classification algorithm. A correlation analysis between extracted physiological features and salivary cortisol levels was also performed. RESULTS: 15 features extracted from heart rate variability, electrodermal, and electroencephalography signals showed a high degree of significance in disentangling stress from a relaxed state. The classification algorithm, based on significant features, provided satisfactory outcomes with 86% accuracy. Furthermore, correlation analysis showed that the observed changes in physiological features were consistent with the trend of salivary cortisol levels (R2 = 0.714). CONCLUSION: The tested set of wearable sensors was able to successfully capture human stress and quantify stress level. SIGNIFICANCE: The results of this pilot study may be useful in designing portable and remote control systems, such as medical devices used to turn on interventions and prevent stress consequences.
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Monitorização Ambulatorial/métodos , Processamento de Sinais Assistido por Computador , Estresse Psicológico/diagnóstico , Dispositivos Eletrônicos Vestíveis , Adulto , Biomarcadores/análise , Eletroencefalografia/instrumentação , Desenho de Equipamento , Feminino , Frequência Cardíaca/fisiologia , Humanos , Hidrocortisona/análise , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial/instrumentação , Saliva/química , Estresse Psicológico/fisiopatologia , Máquina de Vetores de SuporteRESUMO
BACKGROUND & AIMS: Diverticular Disease (DD) is a common clinical condition with a dramatic increasing of the prevalence among industrialized countries. Based on the most used classification, DD may be divided into asymptomatic diverticulosis, symptomatic uncomplicated diverticular disease and complicated diverticular disease. Since recent studies pointed out the role of GUT microbiota imbalance in promoting diverticular formation and inflammation, we have designed a systematic review focusing on the possible role of probiotics in the management of this condition. METHODS: According to PRISMA, we identified studies on DD patients treated with probiotics, by searching on Pubmed, Embase, Cochrane and ResearchGate. RESULTS: 13 studies were included in this review based on our selection criteria: 3 double-blind randomized placebo-controlled, 6 open randomized, and 4 non-randomized open studies. CONCLUSION: This is the first systematic review providing an updated measure of evidence on the efficacy of probiotics in a different phase of DD. Even though the majority of studies are still preliminary, current data show a possible clinical application of certain probiotic strains in all stages of DD. Further investigation is then required to better understand when and how probiotics can be used in different phases of DD.
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Doenças Diverticulares/terapia , Probióticos/uso terapêutico , Doenças Diverticulares/diagnóstico , Doenças Diverticulares/etiologia , HumanosRESUMO
Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows.
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Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials. We evaluated basimglurant, a potent and selective mGluR5 NAM, in a 12-week, double-blind, parallel-group study of 183 adults and adolescents (aged 14-50, mean 23.4 years) with FXS. Individuals with an FMR1 full mutation were randomized to placebo or one of two doses of basimglurant. The primary efficacy endpoint was the change from baseline in behavioral symptoms using the Anxiety Depression and Mood Scale (ADAMS) total score. All treatment arms showed marked behavioral improvements from baseline to week 12 with less improvement in the basimglurant 1.5 mg arm than placebo; however, basimglurant 0.5 mg was inferior to placebo in the ADAMs total score. Treatment with basimglurant was overall well-tolerated. A higher incidence of adverse events classified as psychiatric disorders were reported in patients treated with basimglurant, including three patients with hallucinations or psychosis. In this phase 2 clinical trial, basimglurant did not demonstrate improvement over placebo. Evaluation of the overall risk-benefit in younger patient populations is an important consideration for the design of potential further investigations of efficacy with this class of medications.
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Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Imidazóis/uso terapêutico , Psicotrópicos/uso terapêutico , Piridinas/uso terapêutico , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Adolescente , Adulto , Metilação de DNA , Método Duplo-Cego , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Psicotrópicos/efeitos adversos , Piridinas/efeitos adversos , RNA Mensageiro/sangue , Receptor de Glutamato Metabotrópico 5/metabolismo , Falha de Tratamento , Adulto JovemRESUMO
The present studies examined the role of norepinephrine (NE) system in mediating the enhancement of 5-HT function produced by neurokinin (NK)1 receptor antagonism. Dorsal raphe 5-HT and locus coeruleus NE neurons were recorded in vivo in mice lacking NK1 receptors in wildtype mice pretreated with the NK1 antagonist RP67580 and its inactive enantiomer RP 68651. RP67580 and RP68651 were also tested on 5-HT neurons of mice lacking the 5-HT(1A) receptor. RP67580 increased the firing rate of 5-HT neurons in wildtype mice and in 5-HT(1A) null mutant mice to the same degree, thus indicating that the mechanism by which NK1 antagonists enhances 5-HT firing is independent of 5-HT(1A) receptors. NE neuronal burst activity was increased in NK1 null mutant and wildtype mice given RP67580, but not with RP68651. After NE depletion, RP67580 was ineffective in increasing 5-HT neuronal firing activity in NK1 wildtype mice, and the enhancement of 5-HT neuronal firing observed in NK1 null mutant mice was abolished. In conclusion, NE neurons are essential for the action of NK1 antagonists on 5-HT neurons. In addition, the desensitization of 5-HT(1A) autoreceptors produced by NK1 receptor antagonism is not critical for enhancing 5-HT neuronal firing.
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Antagonistas dos Receptores de Neurocinina-1 , Neurônios/fisiologia , Norepinefrina/fisiologia , Serotonina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Benzilaminas/toxicidade , Interações Medicamentosas , Indóis/farmacologia , Isoindóis , Locus Cerúleo/citologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/lesões , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Núcleos da Rafe/citologia , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/lesões , Receptor 5-HT1A de Serotonina/deficiência , Receptores da Neurocinina-1/deficiência , Serotonina/farmacologiaRESUMO
BACKGROUND: Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-ß (Aß) and removes Aß plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer's disease (AD). METHODS: In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. RESULTS: Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. CONCLUSIONS: The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.
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Doença de Alzheimer/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Fatores Imunológicos/uso terapêutico , Sintomas Prodrômicos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Anticorpos Monoclonais Humanizados , Apolipoproteína E4/genética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
BACKGROUND: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD). OBJECTIVE: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. METHODS: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1âmg, 5âmg, or placebo once daily orally for 52 weeks. RESULTS: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was - 0.15 (pâ=â0.865) and 0.90 (pâ=â0.312) for 1 and 5âmg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1âmg and 5âmg sembragiline groups showed differences in ADCS-ADL of 2.64 (pâ=â0.051) and 1.89 (pâ=â0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: - 2.80 (pâ=â0.014; 1âmg) and - 2.64 (pâ=â0.019; 5âmg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). CONCLUSIONS: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.
Assuntos
Acetamidas/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/uso terapêutico , Pirrolidinonas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-IdadeRESUMO
IMPORTANCE: Antagonism of the postsynaptic metabotropic glutamate subtype 5 receptor is a novel approach to modulate glutamatergic function and has proven efficacy in a number of preclinical behavioral models of depression. OBJECTIVE: To evaluate the safety and efficacy of basimglurant modified-release (MR) vs placebo as adjunctive therapy to ongoing antidepressant medication therapy in patients with MDD who had inadequate response within the current episode. DESIGN, SETTING, AND PARTICIPANTS: In this phase 2b, double blind, randomized clinical trial of 333 adult patients with a DSM-IV-TR diagnosis of MDD across 59 research clinics globally, patients were assigned to 1 of 2 doses of basimglurant MR (0.5 or 1.5 mg) or placebo once daily, adjunctive to ongoing antidepressant medication therapy (selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor). Patients were enrolled from October 5, 2011, through July 26, 2013. INTERVENTIONS: Six-week treatment with 0.5 mg of basimglurant MR, 1.5-mg basimglurant MR, or placebo once daily, adjunctive to ongoing antidepressant medication therapy. MAIN OUTCOMES AND MEASURES: The primary end point was the mean change from baseline score on the Montgomery-Åsberg Depression Rating Scale (MADRS), as rated by the clinician at week 6. Other measures included patient-rated MADRS, Quick Inventory of Depressive Symptomatology-Self-Report, Clinical Global Impression-Improvement, Patient Global Impression-Improvement, and Clinical Global Impression-Severity Scales and adverse events. RESULTS: A total of 596 patients were screened, and 333 were randomized into the study (mean [SD] age, 47 [11.2] years; 216 female [65.1%]). The primary end point (mean change in clinician-rated MADRS score from baseline to end of treatment) was not met (effect size [ES] = 0.16, P = .42; intent-to-treat [ITT] mixed-effects model for repeated measures [MMRM] analysis for comparing 1.5-mg basimglurant MR and placebo). Across secondary and exploratory end points, 1.5-mg basimglurant MR revealed larger improvements vs placebo on the patient-rated MADRS (-16.2 vs -13.3, ES = 0.28, nominal P = .04), Quick Inventory of Depressive Symptomatology-Self-Report (-7.5 vs -5.8; ES = 0.37, nominal P = .009), Clinical Global Impression-Improvement mean score, and Patient Global Impression-Improvement mean score. Improvements were also seen in the patient-rated MADRS remission rate (36.0% vs 22.0%; nominal P = .03) and response rate (50.5% vs 40.4%; nominal P = .13), A 0.5-mg dose of basimglurant MR had no benefit over placebo in any of these measures. The most common adverse event was dizziness, which was mostly transient and of mild intensity. CONCLUSIONS AND RELEVANCE: No difference was observed on the study's primary outcome measure, the clinician-rated MADRS change from baseline to end of treatment, between adjunctive basimglurant MR vs placebo. Adjunctive 1.5-mg basimglurant MR daily revealed, however, an antidepressant effect across secondary end points, particularly in patient-rated measures. These findings combined with good tolerability warrant further investigation with this compound in depressive disorders. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01437657.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Imidazóis/uso terapêutico , Piridinas/uso terapêutico , Adolescente , Adulto , Idoso , Antidepressivos/efeitos adversos , Preparações de Ação Retardada , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Determinação da Personalidade , Piridinas/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND/AIMS: Results of 13C urea breath test (UBT), a noninvasive test for detecting active H. pylori infection, have been regarded also numerically for a possible predictive value on bacterial load and entity of mucosal inflammation. In the present study we wished to determine whether there is a particular value of Delta Over Baseline (DOB) result which could predict resistance to anti-H. pylori therapy. METHODOLOGY: 570 subjects from 1376 tested received a standard triple anti-H. pylori regimen. After a minimum of 6 weeks subjects underwent control UBT testing. Correlation of DOB values at diagnostic and control UBT and sensitivity of different DOB levels to predict resistance to therapy were calculated using simple linear correlation and Bayes' theorem, respectively. RESULTS: Modest linear correlation was observed between DOB values (r2=0.28). The value of 13.0 at diagnostic UBT showed a sensitivity of 65.5% to predict and further positivity at control testing. CONCLUSIONS: In our large series, UBT numerical DOB value weakly predicted resistance to first-line anti-H. pylori therapy.
Assuntos
Testes Respiratórios , Farmacorresistência Bacteriana , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Adulto , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Isótopos de Carbono/análise , Claritromicina/uso terapêutico , Infecções por Helicobacter/diagnóstico , Humanos , Valor Preditivo dos Testes , Inibidores da Bomba de Prótons , Bombas de Próton/uso terapêutico , Falha de Tratamento , Ureia/análiseRESUMO
Depression and anxiety are among the most common diseases in the United States, thus constituting a substantial financial burden for the health care system. Experimental studies of these affective disorders to date have largely focused on the neurotransmitter pathways with well-established pathophysiologic roles, such as serotonergic, noradrenergic, and gamma-aminobutyric acid (GABA)-ergic systems; agents modulating the activity of these pathways are known to be clinically effective. More recently, the neuropeptide substance P (SP) and its receptor (the neurokinin-1 receptor [NK1R]) have been implicated in the pathophysiology of affective disorders, including depression. Earlier preclinical and clinical studies, though, did not provide a clear consensus on the role of SP in the regulation of affective behavior and related pathologic conditions. Recent studies in mice clearly demonstrate that both the genetic disruption and acute pharmacologic blockade of the NK1R result in marked reduction in anxiety-like behavior and stress-related responses. In parallel with these behavioral effects, physiologic changes, such as an increased firing rate of 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nuclei and a desensitization of presynaptic 5-HT1A inhibitory autoreceptors, were observed. These findings provide further evidence for the regulatory role of the SP-NK1R system in modulation of affective behavior and indicate that its effects are mediated, at least in part, via the serotonergic system. Future studies will attempt to delineate the interaction between the SP-NK1R system and various neurotransmitter pathways in greater detail and to address the specific role(s) of this system in different brain regions.
Assuntos
Comportamento Animal/fisiologia , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-1/fisiologia , Afeto/efeitos dos fármacos , Afeto/fisiologia , Animais , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/fisiopatologia , Aprepitanto , Autorreceptores/efeitos dos fármacos , Autorreceptores/fisiologia , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Diazepam/farmacologia , Modelos Animais de Doenças , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Locus Cerúleo/fisiologia , Camundongos , Camundongos Knockout , Morfolinas/farmacocinética , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Atividade Motora/fisiologia , Neurônios/fisiologia , Norepinefrina/fisiologia , Núcleos da Rafe/fisiologia , Receptores da Neurocinina-1/genética , Serotonina/fisiologia , Natação/fisiologiaRESUMO
OBJECTIVE: At present there are no well-established pharmacological approaches in the management of post-cholecystectomy alkaline reactive gastritis. The aim of this study was to assess the effect of sucralfate versus rabeprazole or no treatment on dyspeptic symptoms and endoscopic/histological signs in a population of patients with a history of cholecystectomy and evidence of alkaline reactive gastritis. METHODS: Sixty dyspeptic patients fulfilling the following criteria of inclusion took part in this study: (1) a history of cholecystectomy; (2) no use of anti-inflammatory steroidal and non-steroidal drugs, or abuse of alcohol; (3) evidence of abundant gastric bile reflux at endoscopy; (4) endoscopic signs of chronic gastritis; (5) histological signs of chronic gastritis; and (6) absence of Helicobacter pylori infection. Dyspeptic symptoms were evaluated by means of a self-administered validated questionnaire. Patients included in the study were randomly assigned to one of three treatment groups for 3 months: sucralfate, rabeprazole, observation. Patients were re-evaluated at the end of the treatment. RESULTS: Sucralfate and rabeprazole therapies were both able to significantly reduce epigastric pain, heartburn, bloating and halitosis. Endoscopic/histological signs were lower in both treatment groups compared to the observation group. CONCLUSION: Both sucralfate and rabeprazole therapies are effective treatment options in the patients with alkaline gastritis when compared with observation.