25 results on '"Encenicline"'
Search Results
2. The Novel Antipsychotic Drug Cariprazine and Cognition Enhancing Drugs: Indications for their Use as the Add-on Therapy in Schizophrenia
- Author
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Rafael Coveñas and Felix-Martin Werner
- Subjects
Psychosis ,medicine.medical_treatment ,Cariprazine ,Schizoaffective disorder ,Bioinformatics ,Piperazines ,chemistry.chemical_compound ,Cognition ,Drug Discovery ,medicine ,Lumateperone ,Humans ,Antipsychotic ,Clozapine ,Pharmacology ,Encenicline ,business.industry ,medicine.disease ,Treatment Outcome ,chemistry ,Pharmaceutical Preparations ,Schizophrenia ,Quality of Life ,business ,medicine.drug ,Antipsychotic Agents - Abstract
Background: Schizophrenia and schizoaffective disorder are treated with antipsychotic drugs. Some patients show treatment-resistant forms of psychotic disorders, and in this case, they can be treated with clozapine. Based on the previous reviews on novel antipsychotic drugs, it is important to know whether the add-on therapy with the new drugs can ameliorate the positive and negative schizophrenic scale (PANSS) total score. Objective: The aim of this review is to suggest an appropriate treatment for patients with treatment-resistant forms of psychotic disorders. A combination of the currently available antipsychotic drugs with novel antipsychotic or modulating drugs might improve negative schizophrenic symptoms and cognitive function and thereby social functioning and quality of life. Results: The mechanisms of action, the therapeutic effects, and the pharmacokinetic profiles of novel antipsychotic drugs such as cariprazine, brexipiprazole, and lumateperone have been updated. Published case reports of patients with treatment-resistant psychoses have also been discussed in this study. These patients were treated only with clozapine, as a result of which a high PANSS total score was observed. Only the add-on therapy with cariprazine improved the score, and above all, the negative schizophrenic symptoms and cognitive functions were improved. For the ensurance of a constant antipsychotic drug concentration, long-acting injectable antipsychotic drugs might be a choice for the maintenance therapy in schizophrenia. New modulating drugs, such as receptor positive allosteric modulators (N-methyl-D-aspartate receptor; subtype 5 of the metabotropic glutamatergic receptor) and encenicline, an alpha7 nicotinic cholinergic receptor agonist, have been investigated in preclinical and clinical trials. Conclusion: In clinical trials, patients with treatment-resistant forms of psychosis should be examined to know whether combination therapy with clozapine and a novel antipsychotic drug can ameliorate the PANSS total score. In schizophrenia, long-acting injectable antipsychotic drugs are safe and tolerable maintenance therapy. In further clinical studies, it should be investigated whether patients with treatment-resistant forms of psychoses can improve negative schizophrenic symptoms and cognitive functions by the add-on therapy with cognitionenhancing drugs.
- Published
- 2020
3. Phase IIb Trial of an α7 Nicotinic Receptor Partial Agonist With and Without Nicotine Patch for Withdrawal-Associated Cognitive Deficits and Tobacco Abstinence
- Author
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Vicenta Hudziak, Mireya Nadal, Ailish Hanly, David Mischoulon, Corinne Cather, A. Eden Evins, Luke E. Stoeckel, Sara Sobolewski, Haiyue Zhang, Elisabeth B Dodds, Randi M. Schuster, Gladys N. Pachas, Christine A. Ulysse, David A. Schoenfeld, and Maurizio Fava
- Subjects
Adult ,Male ,Nicotine ,alpha7 Nicotinic Acetylcholine Receptor ,media_common.quotation_subject ,Nicotine patch ,medicine.medical_treatment ,Placebo ,Partial agonist ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Humans ,Medicine ,Cognitive Dysfunction ,Pharmacology (medical) ,Nicotinic Agonists ,media_common ,Tobacco Use Cessation ,Encenicline ,business.industry ,Abstinence ,Nicotine replacement therapy ,medicine.disease ,Tobacco Use Cessation Devices ,Substance Withdrawal Syndrome ,030227 psychiatry ,Psychiatry and Mental health ,Nicotine withdrawal ,Anesthesia ,Drug Therapy, Combination ,Female ,business ,030217 neurology & neurosurgery - Abstract
Purpose/background The objective of this study was to determine whether a novel α7 nicotinic acetylcholine receptor partial agonist improves cognition during nicotine withdrawal and improves abstinence rates. To do so, the effect of the α7 nicotinic acetylcholine receptor partial agonist, encenicline, on cognition and abstinence was evaluated when given as monotherapy and when combined with transdermal nicotine patch (nicotine replacement therapy [NRT]). Methods Adult daily smokers, n = 160, who were motivated to quit smoking completed cognitive testing at satiated baseline and after overnight abstinence and then were randomized to receive a 12-week trial of encenicline 1 mg twice daily or identical placebo the day of the overnight abstinent cognitive testing. In the first 6 weeks of the 12-week encenicline administration, participants were also randomized to 6 weeks of NRT patch or placebo patch. Primary outcomes were cognition during abstinence and 7-day point-prevalence abstinence at week 12. Results No beneficial effects of encenicline were observed on cognition or abstinence when compared with placebo or when combined with NRT compared with placebo capsule + NRT. Of the 4 conditions, abstinence rates were lowest among those assigned to encenicline alone. Conclusions Beneficial effects of NRT were observed on cognitive and abstinence outcomes when combined with encenicline compared with encenicline plus placebo patch. Addition of NRT to encenicline improved odds of abstinence approximately 3-fold compared with encenicline plus placebo patch. We conclude that encenicline, 1 mg/d, did not improve abstinence-associated cognitive impairment or abstinence rates as monotherapy or adjunctive therapy to NRT patch.
- Published
- 2018
4. 32.2 TWO GLOBAL PHASE III TRIALS OF ENCENICLINE FOR COGNITIVE IMPAIRMENT IN CHRONIC SCHIZOPHRENIA PATIENTS: RED FLAGS AND LESSONS LEARNED
- Author
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Stephen Brannan
- Subjects
Plenary/Symposia ,Psychiatry and Mental health ,medicine.medical_specialty ,Encenicline ,Phase iii trials ,business.industry ,Medicine ,Chronic schizophrenia ,business ,Psychiatry ,Cognitive impairment ,Red flags - Abstract
BACKGROUND: Multiple lines of evidence indicate that alterations of the α7 nicotinic acetylcholine receptor (nAChR) may play a role in the pathophysiology of several neuropsychiatric disorders that manifest with cognitive impairment, including schizophrenia. Encenicline (EVP-6124), a selective α7 nAChR showed promising biomarker and clinical evidence for cognitive improvement as well as functional co-primaries in Phase II trials. Positive results led to the launch of two global Phase III trials (EVP-6124-015/016) aimed at assessing the efficacy and safety of once-daily encenicline tablets as a pro-cognitive treatment in stable patients with schizophrenia. Our primary hypothesis was that encenicline would demonstrate efficacy for the improvement of performance on the MATRICS Consensus Cognitive Battery (MCCB) and for ratings on the Schizophrenia Cognition Rating Scale (SCoRS). A detailed examination of factors with the potential to impact the trial results are ongoing (e.g., background antipsychotic medication, treatment adherence, and demographic variables) for purposes of evaluating concluding results and to inform later clinical development programs of any ‘red flags’ and key lessons learned. METHODS: Two 6-month, randomized, double-blind, placebo-controlled, parallel-dosing, Phase III studies evaluated EVP-6124 versus placebo, as a pro-cognitive treatment in individuals with schizophrenia on chronic, stable, atypical antipsychotic therapy. Study methodologies were identical with the exception of geographical participation. A screening period of up to 28 days occurred as placebo run-in were individuals were assessed for their eligibility based upon pill count compliance over a 14-day period and ability to complete the MCCB cognitive battery. Eligible subjects (total n = 1,520, across both trials) continued their usual antipsychotic regimen and were randomly assigned 1:1:1 on Study Day 1 to receive 1 of 3 double-blind treatments: once-daily EVP-6124 HCl tablets (1 or 2 mg) or placebo for 26 weeks (Study Days 1 to 182). The MCCB battery was completed once during placebo run-in, at baseline, 4, 8, 12, and 26-week study visits. RESULTS: Robust improvements were observed in both trials on the NeuroCognitive Composite Score (NCC; all MCCB tests except the MCEIT) and the SCoRS across all treatment groups, from screening through to baseline visit and from baseline through to week 26. However no statistically significant difference between encenicline and placebo emerged using a Mixed Model Repeated Measures change from baseline to week 26 analysis, for either NCC or SCoRS. Although in study EVP-6124-016 there was a small trend for both the 1 and 2mg groups to be greater than placebo for NCC. Encenicline was generally safe and well tolerated with adverse events reported by approximately 50% of the patients; mild constipation was most frequent. Post-hoc analyses (on-going) on pooled data from both trials are examining the effects of adherence on treatment efficacy, site effects (including experience on the part of both assessors and patients), and the impact of various demographic variables (race and geographic location) and treatment (type of anti-psychotic medication). CONCLUSIONS: The results from these two large Phase III studies, showed limited benefit of encenicline for the treatment of cognitive impairment and related functional deficits in people with schizophrenia. However, a number of valuable observations were obtained from these trials which question whether the Phase III results are less reflective of the true efficacy of encenicline than the phase II studies previously indicated. These include: 1) the importance of accounting for/mitigating non-adherence to treatment, 2) multiple repeated MCCB testing sessions did not plateau learning effects and 3) subjects with greater change in Outcome scores from screening to baseline also showed aberrant changes from baseline to week 26 compared to subjects with smaller changes prior to baseline, inherently reducing signal:noise ratio. Results of additional post-hoc analyses will be discussed to guide and inform the future development of CIAS clinical trials.
- Published
- 2019
5. Aged rhesus monkeys: Cognitive performance categorizations and preclinical drug testing
- Author
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Patrick M. Callahan, David Blake, Wayne D. Beck, Alvin V. Terry, and Marc Plagenhoef
- Subjects
Male ,0301 basic medicine ,Aging ,Quinuclidines ,medicine.medical_specialty ,Drug Evaluation, Preclinical ,Thiophenes ,Disease ,Audiology ,Partial agonist ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Cognition ,0302 clinical medicine ,Animals ,Medicine ,Cognitive Dysfunction ,Effects of sleep deprivation on cognitive performance ,Pathological ,Nootropic Agents ,Pharmacology ,Encenicline ,business.industry ,Macaca mulatta ,Memory, Short-Term ,030104 developmental biology ,Nicotinic agonist ,Drug development ,Female ,business ,030217 neurology & neurosurgery - Abstract
Rodent models have facilitated major discoveries in neurobiology, however, the low success rate of novel medications in clinical trials have led to questions about their translational value in neuropsychiatric drug development research. For age-related disorders of cognition such as Alzheimer’ disease (AD) there is interest in moving beyond transgenic amyloid-β and/or tau-expressing rodent models and focusing more on natural aging and dissociating “healthy” from “pathological” aging to identify new therapeutic targets and treatments. In complex disorders such as AD, it can also be argued that animals with closer neurobiology to humans (e.g., nonhuman primates) should be employed more often particularly in the later phases of drug development. The purpose of the work described here was to evaluate the cognitive capabilities of rhesus monkeys across a wide range of ages in different delayed response tasks, a computerized delayed match to sample (DMTS) task and a manual delayed match to position (DMTP) task. Based on specific performance criteria and comparisons to younger subjects, the older subjects were generally less proficient, however, some performed as well as young subjects, while other aged subjects were markedly impaired. Accordingly, the older subjects could be categorized as aged “cognitively-unimpaired” or aged “cognitively-impaired” with a third group (aged-other) falling in between. Finally, as a proof of principle, we demonstrated using the DMTP task that aged cognitively-impaired monkeys are sensitive to the pro-cognitive effects of a nicotinic acetylcholine receptor (nAChR) partial agonist, encenicline, suggesting that nAChR ligands remain viable as potential treatments for age-related disorders of cognition.
- Published
- 2021
6. Hippocampal network dynamics in response to α7 nACh receptors activation in amyloid-β overproducing transgenic mice
- Author
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Dávid Nagy, Milan Stoiljkovic, Gerhard Koenig, Mihály Hajós, Gábor Patrick Hajós, Craig Kelley, and Liza Leventhal
- Subjects
Male ,0301 basic medicine ,Agonist ,Genetically modified mouse ,Quinuclidines ,Aging ,alpha7 Nicotinic Acetylcholine Receptor ,medicine.drug_class ,Hippocampus ,Mice, Transgenic ,Thiophenes ,Hippocampal formation ,Pharmacology ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Alzheimer Disease ,medicine ,Animals ,Gamma Rhythm ,Molecular Targeted Therapy ,Theta Rhythm ,Receptor ,Encenicline ,Amyloid beta-Peptides ,Chemistry ,General Neuroscience ,Wild type ,medicine.disease ,030104 developmental biology ,Female ,Neurology (clinical) ,Nerve Net ,Geriatrics and Gerontology ,Alzheimer's disease ,Neuroscience ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Amyloid-β (Aβ) peptide overproduction is one of the pathomechanisms contributing to Alzheimer's disease (AD). Agonists of α7 nicotinic acetylcholine receptors (α7 nAChRs) are under development as symptomatic treatments for AD, and clinical findings suggest that α7 nAChR agonists may improve cognitive functions in AD patients. However, interactions between Aβ and α7 nAChRs have been observed, implying that high levels of Aβ may modify the effects of α7 nAChR agonists. Therefore, we tested the α7 nAChR agonist FRM-17874, an analogue of encenicline, in 8-month-old Aβ overproducing 5xFAD mice in an in vivo neurophysiological assay with a high construct and predictive validity for testing procognitive drugs. By recording changes in brainstem-stimulation-elicited hippocampal oscillations, we identified previously undescribed neurophysiological impairments in 5xFAD mice, including significantly decreased power of theta and gamma oscillations and theta-phase-gamma-amplitude coupling. Compared with their saline controls, systemically administered FRM-17874 significantly increased stimulation-induced theta power by 30% in both 5xFAD and wild-type mice. However, FRM-17874 did not impact gamma oscillation or theta-phase-gamma-amplitude coupling in either wild type or 5xFAD mice, and it did not eliminate the significant differences in these parameters between the 2 groups.
- Published
- 2016
7. Attenuated Mismatch Negativity in Attenuated Psychosis Syndrome Predicts Psychosis: Can Galantamine-Memantine Combination Prevent Psychosis?
- Author
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Maju Mathew Koola
- Subjects
Psychosis ,Encenicline ,business.industry ,Short Communication ,Memantine ,Mismatch negativity ,General Medicine ,medicine.disease ,Partial agonist ,behavioral disciplines and activities ,030227 psychiatry ,03 medical and health sciences ,0302 clinical medicine ,Nicotinic agonist ,Schizophrenia ,medicine ,Galantamine ,business ,Neuroscience ,030217 neurology & neurosurgery ,psychological phenomena and processes ,medicine.drug - Abstract
Although first proposed in 1987, early diagnosis and intervention of psychotic disorders has only recently become a priority in the field. The interest in clinical high risk (CHR) for psychosis skyrocketed after attenuated psychosis syndrome (APS) was added to the DSM-5. There is evidence that in individuals with APS, attenuated mismatch negativity (MMN: functioning of the auditory sensory memory system) is a robust biomarker that can predict transition to psychosis. The underlying pathophysiological mechanism of MMN is via the interaction of N-methyl-D-aspartate (NMDA) and alpha-7 nicotinic acetylcholine (α-7nACh) receptors. Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the α-7nACh receptors. Memantine is an NMDA receptor antagonist. Memantine has been shown to enhance MMN in people with schizophrenia. Although no studies with galantamine have measured MMN, encenicline, an α-7 nicotinic partial agonist, increased MMN in people with schizophrenia. MMN has been suggested as a potential biomarker with the galantamine-memantine combination for the treatment of neuropsychiatric disorders. Hence, the galantamine-memantine combination may enhance MMN, thereby preventing CHR to psychosis. With no treatments available, randomized controlled trials are warranted with the galantamine-memantine combination to delay or prevent conversion to psychosis in individuals with CHR.
- Published
- 2018
8. Targeting of α7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia and the Use of Auditory Sensory Gating as a Translational Biomarker
- Author
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Kenji Hashimoto
- Subjects
Quinuclidines ,auditory sensory gating ,allosteric positive modulators ,alpha7 Nicotinic Acetylcholine Receptor ,Pyridines ,Allosteric regulation ,Disease ,Pharmacology ,Benzylidene Compounds ,Article ,Thiadiazoles ,mental disorders ,Drug Discovery ,medicine ,Animals ,Humans ,Acetylcholine receptor ,Encenicline ,Sensory gating ,business.industry ,Sensory Gating ,medicine.disease ,schizophrenia ,medicine.anatomical_structure ,Nicotinic agonist ,Schizophrenia ,Evoked Potentials, Auditory ,α7 nicotinic acetylcholine receptors ,biomarker ,Biomarker (medicine) ,agonists ,business ,Biomarkers ,Antipsychotic Agents - Abstract
Accumulating evidence suggests that the α7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a key role in inflammatory processes, thought to be involved in the pathophysiology of neuropsychiatric diseases, such as schizophrenia and Alzheimer's disease. Preclinical and clinical studies showed that the diminished suppression of P50 auditory evoked potentials in patients with schizophrenia may be associated with a decreased density of α7 nAChRs in the brain. This points to a role for auditory sensory gating (P50) as a translational biomarker. A number of agonists and positive allosteric modulators (PAMs) for α7 nAChR promoted beneficial effects in animal models with sensory gating and cognitive deficits. Additionally, several clinical studies showed that α7 nAChR agonists could improve suppression in auditory P50 evoked potentials, as well as cognitive deficits, and negative symptoms in patients with schizophrenia. Taken together, α7 nAChR presents as an extremely attractive therapeutic target for schizophrenia. In this article, the author discusses recent findings on α7 nAChR agonists such as DMXB-A, RG3487, TC-5619, tropisetron, EVP-6124 (encenicline), ABT-126, AQW051 and α7 nAChR PAMs such as JNJ-39393406, PNU- 120596 and AVL-3288 (also known as UCI-4083), and their potential as therapeutic drugs for neuropsychiatric diseases, such as schizophrenia.
- Published
- 2015
9. Randomized, Double-Blind, Placebo-Controlled Study of Encenicline, an α7 Nicotinic Acetylcholine Receptor Agonist, as a Treatment for Cognitive Impairment in Schizophrenia
- Author
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Hans J Moebius, Richard S.E. Keefe, Dana Hilt, Herbert A Meltzer, Gerhard Koenig, Ilise Lombardo, Nancy Dgetluck, and Maria Gawryl
- Subjects
Adult ,Male ,Quinuclidines ,medicine.medical_specialty ,Adolescent ,alpha7 Nicotinic Acetylcholine Receptor ,Population ,Placebo-controlled study ,Thiophenes ,Placebo ,Young Adult ,Cognition ,Double-Blind Method ,Rating scale ,Internal medicine ,medicine ,Humans ,Nicotinic Agonists ,education ,Psychiatric Status Rating Scales ,Pharmacology ,Psychotropic Drugs ,education.field_of_study ,Encenicline ,Positive and Negative Syndrome Scale ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,Treatment Outcome ,Schizophrenia ,Female ,Schizophrenic Psychology ,Cognition Disorders ,Psychology ,Antipsychotic Agents ,Clinical psychology - Abstract
Encenicline is a novel, selective α7 nicotinic acetylcholine receptor agonist in development for treating cognitive impairment in schizophrenia and Alzheimer's disease. A phase 2, double-blind, randomized, placebo-controlled, parallel-design, multinational study was conducted. Patients with schizophrenia on chronic stable atypical antipsychotics were randomized to encenicline 0.27 or 0.9 mg once daily or placebo for 12 weeks. The primary efficacy end point was the Overall Cognition Index (OCI) score from the CogState computerized battery. Secondary end points include MATRICS Consensus Cognitive Battery (MCCB) (in US patients), the Schizophrenia Cognition Rating Scale (SCoRS) total score, SCoRS global rating, and Positive and Negative Syndrome Scale (PANSS) total and subscale and cognition factor scores. Of 319 randomized patients, 317 were included in the safety population, and 307 were included in the intent-to-treat population. Notable trends in improvement were demonstrated across all cognition scales. For the OCI score, the LS mean difference for encenicline 0.27 mg vs placebo was significant (Cohen's d=0.257; P=0.034). Mean SCoRS total scores decreased showing improvement in function over time, and the difference was significant for encenicline 0.9 mg vs placebo (P=0.011). Furthermore, the difference between encenicline 0.9 mg and placebo was significant for the PANSS Cognition Impairment Domain (P=0.0098, Cohen's d=0.40) and for the PANSS Negative scale (P=0.028, Cohen's d=0.33). Treatment-emergent adverse events were reported at similar frequencies across all treatment groups (39.0% with placebo, 23.4% with encenicline 0.27 mg, and 33.3% with encenicline 0.9 mg). Overall, encenicline was generally well tolerated and demonstrated clinically meaningful improvements in cognition and function in patients with schizophrenia.
- Published
- 2015
10. Reliability, validity and treatment sensitivity of the Schizophrenia Cognition Rating Scale
- Author
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Thomas D. Patterson, Dana Hilt, Philip D. Harvey, Nathan B. Spagnola, Richard S.E. Keefe, Stacy A. Ruse, Meera Narasimhan, Vicki G. Davis, and Nancy Dgetluck
- Subjects
Adult ,Male ,medicine.medical_specialty ,Psychometrics ,alpha7 Nicotinic Acetylcholine Receptor ,Context (language use) ,Sensitivity and Specificity ,Article ,Cognition ,Rating scale ,Interview, Psychological ,medicine ,Humans ,Pharmacology (medical) ,Effects of sleep deprivation on cognitive performance ,Psychiatry ,Biological Psychiatry ,Psychiatric Status Rating Scales ,Pharmacology ,Encenicline ,Neuropsychology ,Reproducibility of Results ,medicine.disease ,United States ,Europe ,Clinical trial ,Psychiatry and Mental health ,Neurology ,Schizophrenia ,Female ,Schizophrenic Psychology ,Neurology (clinical) ,Cognition Disorders ,Factor Analysis, Statistical ,Psychology ,Antipsychotic Agents ,Clinical psychology - Abstract
Cognitive functioning can be assessed with performance-based assessments such as neuropsychological tests and with interview-based assessments. Both assessment methods have the potential to assess whether treatments for schizophrenia improve clinically relevant aspects of cognitive impairment. However, little is known about the reliability, validity and treatment responsiveness of interview-based measures, especially in the context of clinical trials. Data from two studies were utilized to assess these features of the Schizophrenia Cognition Rating Scale (SCoRS). One of the studies was a validation study involving 79 patients with schizophrenia assessed at 3 academic research centers in the US. The other study was a 32-site clinical trial conducted in the US and Europe comparing the effects of encenicline, an alpha-7 nicotine agonist, to placebo in 319 patients with schizophrenia. The SCoRS interviewer ratings demonstrated excellent test-retest reliability in several different circumstances, including those that did not involve treatment (ICC> 0.90), and during treatment (ICC>0.80). SCoRS interviewer ratings were related to cognitive performance as measured by the MCCB (r=-0.35), and demonstrated significant sensitivity to treatment with encenicline compared to placebo (P
- Published
- 2015
11. Tropisetron and its targets in Alzheimer’s disease
- Author
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Kenji Hashimoto
- Subjects
Agonist ,Drug ,Quinuclidines ,Indoles ,alpha7 Nicotinic Acetylcholine Receptor ,medicine.drug_class ,media_common.quotation_subject ,α7 Nicotinic receptor ,Tropisetron ,Clinical Biochemistry ,Thiophenes ,Pharmacology ,Alzheimer Disease ,mental disorders ,Drug Discovery ,medicine ,Amyloid precursor protein ,Animals ,Humans ,Nicotinic Agonists ,Donepezil ,media_common ,Inflammation ,Encenicline ,biology ,business.industry ,Memantine ,Mild cognitive impairment ,Alzheimer's disease ,Receptor antagonist ,5-HT3 receptor ,biology.protein ,Molecular Medicine ,Serotonin Antagonists ,β-Amyloid ,business ,medicine.drug - Abstract
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Despite this, there are no drugs for preventing the onset of AD. Preclinical studies suggest that the interaction between amyloid-β peptides (Aβ) and the α7 nicotinic acetylcholine receptor (α7 nAChR) plays a key role in AD pathology, and that α7 nAChR agonists could act as potential therapeutic drugs for AD. A recent study demonstrated that tropisetron, a potent α7 nAChR agonist and serotonin 5-hydroxytryptamine3 receptor antagonist, also bound to the ectodomain of amyloid precursor protein. Furthermore, tropisetron promoted greater improvements in memory than current AD therapeutic drugs, such as memantine and donepezil. Positron emission tomography studies detected Aβ deposition and inflammation in the brains of subjects with amnestic mild cognitive impairment (MCI) before the onset of AD. Given the role of α7 nAChR in Aβ deposition and inflammation, tropisetron represents an attractive potential therapeutic drug to delay or prevent MCI and AD. Additionally as this drug is used internationally to treat chemotherapy-induced emesis, its safety record is already known.
- Published
- 2014
12. The Novel Antipsychotic Drug Cariprazine and Cognition Enhancing Drugs: Indications for their Use as the Add-on Therapy in Schizophrenia.
- Author
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Werner FM and Coveñas R
- Subjects
- Cognition, Humans, Piperazines, Quality of Life, Treatment Outcome, Antipsychotic Agents therapeutic use, Pharmaceutical Preparations, Schizophrenia drug therapy
- Abstract
Background: Schizophrenia and schizoaffective disorder are treated with antipsychotic drugs. Some patients show treatment-resistant forms of psychotic disorders, and in this case, they can be treated with clozapine. Based on the previous reviews on novel antipsychotic drugs, it is important to know whether the add-on therapy with the new drugs can ameliorate the positive and negative schizophrenic scale (PANSS) total score., Objectives: The aim of this review is to suggest an appropriate treatment for patients with treatment-resistant forms of psychotic disorders. A combination of the currently available antipsychotic drugs with novel antipsychotic or modulating drugs might improve negative schizophrenic symptoms and cognitive function and thereby social functioning and quality of life., Results: The mechanisms of action, the therapeutic effects, and the pharmacokinetic profiles of novel antipsychotic drugs such as cariprazine, brexipiprazole, and lumateperone have been updated. Published case reports of patients with treatment-resistant psychoses have also been discussed in this study. These patients were treated only with clozapine, as a result of which a high PANSS total score was observed. Only the add-on therapy with cariprazine improved the score, and above all, the negative schizophrenic symptoms and cognitive functions were improved. For the ensurance of a constant antipsychotic drug concentration, long-acting injectable antipsychotic drugs might be a choice for the maintenance therapy in schizophrenia. New modulating drugs, such as receptor positive allosteric modulators (N-methyl-D-aspartate receptor; subtype 5 of the metabotropic glutamatergic receptor) and encenicline, an alpha7 nicotinic cholinergic receptor agonist, have been investigated in preclinical and clinical trials., Conclusion: In clinical trials, patients with treatment-resistant forms of psychosis should be examined to know whether combination therapy with clozapine and a novel antipsychotic drug can ameliorate the PANSS total score. In schizophrenia, long-acting injectable antipsychotic drugs are safe and tolerable maintenance therapy. In further clinical studies, it should be investigated whether patients with treatment-resistant forms of psychoses can improve negative schizophrenic symptoms and cognitive functions by the add-on therapy with cognitionenhancing drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2021
- Full Text
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13. Partial agonism at the α7 nicotinic acetylcholine receptor improves attention, impulsive action and vigilance in low attentive rats
- Author
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Andrew Hayward, Joanna C. Neill, and Lisa Adamson
- Subjects
Male ,Quinuclidines ,alpha7 Nicotinic Acetylcholine Receptor ,media_common.quotation_subject ,Stimulus (physiology) ,Partial agonist ,Choice Behavior ,Developmental psychology ,Nicotine ,03 medical and health sciences ,0302 clinical medicine ,α7 nicotinic acetylcholine receptor ,Thiadiazoles ,medicine ,Animals ,Pharmacology (medical) ,Agonism ,Attention ,Biological Psychiatry ,media_common ,Pharmacology ,Encenicline ,Analysis of Variance ,Dose-Response Relationship, Drug ,030227 psychiatry ,Rats ,Psychiatry and Mental health ,Disease Models, Animal ,Neurology ,Attention Deficit Disorder with Hyperactivity ,Impulsive Behavior ,Female ,Neurology (clinical) ,Rats, Transgenic ,Psychology ,Neuroscience ,α7 nachr ,030217 neurology & neurosurgery ,Photic Stimulation ,Vigilance (psychology) ,medicine.drug - Abstract
Inattention is a disabling symptom in conditions such as schizophrenia and attention deficit/hyperactivity disorder. Nicotine can improve attention and vigilance, but is unsuitable for clinical use due to abuse liability. Genetic knockout of the α7 nicotinic acetylcholine receptor (nAChR) induces attention deficits therefore selective agonism may improve attention, without the abuse liability associated with nicotine. The α7 nAChR partial agonist encenicline (formerly EVP-6124) enhances memory in rodents and humans. Here we investigate, for the first time, efficacy of encenicline to improve attention and vigilance in animals behaviourally grouped for low attentive traits in the 5 choice-continuous performance task (5C-CPT). Female Lister Hooded rats were trained to perform the 5C-CPT with a variable stimulus duration (SD). Animals were then grouped based on performance into upper and lower quartiles of d′ (vigilance) and accuracy (selective attention), producing high-attentive (HA) and low-attentive (LA) groups. LA animals showed an increase in selective attention and vigilance at 0.3 mg/kg encenicline, a reduction in impulsive action (probability of false alarms) and increase in vigilance following 1 mg/kg at 0.75 s SD. At 1 mg/kg, HA animals had reduced selective attention at 0.75 s SD and reduced vigilance at 0.75 and 1.25 s SD. Improvement of attention, vigilance and impulsive action in LA animals demonstrates that encenicline has pro-attentive properties dependent on baseline levels of performance. Our work suggests that α7 nAChR partial agonism may improve attention particularly in conditions with low attention.
- Published
- 2016
14. Therapeutic improvements expected in the near future for schizophrenia and schizoaffective disorder: an appraisal of phase III clinical trials of schizophrenia-targeted therapies as found in US and EU clinical trial registries
- Author
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Morten S. Thomsen, Leslie Citrome, Chen-Chung Liu, Ludovic Samalin, Ricardo P. Garay, Christoph U. Correll, Ahcène Hameg, Pierre-Michel Llorca, Centre d'accueil et d'échanges scientifiques internationaux [Villemoisson-sur-Orge, France] (CRAVEN), Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Graduate Institute of Network Learning Technology, National Central University [Taiwan] (NCU), Psychiatric Department, and Sanofi-Aventis
- Subjects
medicine.medical_specialty ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Cariprazine ,Schizoaffective disorder ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,media_common.cataloged_instance ,Humans ,Pharmacology (medical) ,Valbenazine ,European Union ,Registries ,European union ,Psychiatry ,ComputingMilieux_MISCELLANEOUS ,Brexpiprazole ,media_common ,Pharmacology ,Encenicline ,[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior ,business.industry ,[SCCO.NEUR]Cognitive science/Neuroscience ,[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences ,General Medicine ,medicine.disease ,United States ,030227 psychiatry ,3. Good health ,Clinical trial ,chemistry ,Clinical Trials, Phase III as Topic ,Psychotic Disorders ,Schizophrenia ,Schizophrenic Psychology ,business ,Cognition Disorders ,030217 neurology & neurosurgery ,Antipsychotic Agents - Abstract
In this review, the authors describe medications in phase III of clinical development for schizophrenia and schizoaffective disorder, and provide an opinion on how current treatment can be improved in the near future.Recent (post 2013) phase III clinical trials of schizophrenia-targeted therapies were found in US and EU clinical trial registries. Two hundred fifty-three trials were identified, that included 16 investigational compounds. The antipsychotics brexpiprazole and cariprazine have been approved in the US, and although both are dopamine D2 receptor partial agonists, they differ markedly in their pharmacodynamic profiles. Encenicline and valbenazine are first-in-class candidates for treatment of cognitive impairment associated with schizophrenia (CIAS) and tardive dyskinesia, respectively. Eleven add-on compounds were previously approved for other therapeutic indications and are for the most part being studied at academic medical centers and smaller pharmaceutical companies for negative symptoms and CIAS or for specific populations (comorbidities, antipsychotic-induced obesity).Promising new agents are emerging for schizophrenia and schizoaffective disorder. In addition to better-tolerated antipsychotics that treat positive symptoms, we could see the arrival of the first effective drug for negative symptoms and CIAS, which would strongly facilitate the ultimate goal of recovery in persons with schizophrenia.
- Published
- 2016
15. Current Approaches Against Alzheimer's Disease in Clinical Trials
- Author
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Kuca,Kamil, Soukup,Ondrej, Maresova,Petra, Korabecny,Jan, Nepovimova,Eugenie, Klimova,Blanka, Honegr,Jan, Ramalho,Teodorico C., and França,Tanos C. C.
- Subjects
AC-42 ,epigallocatechin gallate ,treatment ,encenicline ,semagacestat ,tacrine ,huperzine A ,ABT-126 ,atorvastatin ,Alzheimer's disease ,donepezil ,arecoline ,rosiglitazone ,tideglusib ,minocycline ,etazolate ,rivastigmine ,valproic acid ,thalidomide ,pioglitazone ,methylene blue ,tramiprosate ,immunotherapy ,galantamine - Abstract
Alzheimer's disease (AD) is a progressive degenerative brain disease which causes mental and physical decline, gradually resulting in death. Currently, this disease represents one of the uppermost human issues, both from the medical and economic point of view. Interest in the discovery of a drug for AD is enormous. However, despite the long-term and worldwide effort for a more effective therapy, the only available treatment is a symptomatic use of acetylcholinesterase inhibitors (AChEIs) and memantine. New therapeutic approaches as well as those based on cholinergic or amyloid theory have not brought the desired benefits yet. Thus, the question is whether an effective drug for this progressive disease will ever be developed or whether people will have to rely only on prevention and minimize risk factors of AD.
- Published
- 2016
16. Current Approaches Against Alzheimer's Disease in Clinical Trials
- Author
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Teodorico C. Ramalho, Eugenie Nepovimova, Kamil Kuca, Petra Maresova, Jan Korabecny, Jan Honegr, Ondrej Soukup, Tanos C. C. França, and Blanka Klimova
- Subjects
0301 basic medicine ,Rivastigmine ,medicine.medical_specialty ,Encenicline ,business.industry ,Memantine ,General Chemistry ,Disease ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,Galantamine ,Intensive care medicine ,Donepezil ,business ,030217 neurology & neurosurgery ,Progressive disease ,medicine.drug ,Semagacestat - Abstract
Alzheimer's disease (AD) is a progressive degenerative brain disease which causes mental and physical decline, gradually resulting in death. Currently, this disease represents one of the uppermost human issues, both from the medical and economic point of view. Interest in the discovery of a drug for AD is enormous. However, despite the long-term and worldwide effort for a more effective therapy, the only available treatment is a symptomatic use of acetylcholinesterase inhibitors (AChEIs) and memantine. New therapeutic approaches as well as those based on cholinergic or amyloid theory have not brought the desired benefits yet. Thus, the question is whether an effective drug for this progressive disease will ever be developed or whether people will have to rely only on prevention and minimize risk factors of AD.
- Published
- 2016
17. EVP-6124, a novel and selective alpha 7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of alpha 7 nicotinic acetylcholine receptors
- Author
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Nick P. van Goethem, Frank G. Boess, Gerhard Konig, Olga A.H. Reneerkens, Dana Hilt, Richard Chesworth, Daniel Bertrand, Jos Prickaerts, Gideon Shapiro, Sonia Bertrand, Maria Gawryl, Christoph Methfessel, Dorothy G. Flood, RS: MHeNs School for Mental Health and Neuroscience, Psychiatrie & Neuropsychologie, and Promovendi MHN
- Subjects
Male ,Quinuclidines ,alpha7 Nicotinic Acetylcholine Receptor ,Thiophenes ,Pharmacology ,Receptors, Nicotinic ,Partial agonist ,Acetylcholine esterase inhibitor ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Novel mechanism of action ,Piperidines ,Memory ,medicine ,Animals ,Donepezil ,Nicotinic Agonists ,Rats, Wistar ,Acetylcholine receptor ,Methyllycaconitine ,Object recognition task ,Encenicline ,Dose-Response Relationship, Drug ,Antagonist ,Brain ,Long-term potentiation ,alpha 7 nAChR ,Rats ,Drug Partial Agonism ,Nicotinic agonist ,chemistry ,Indans ,Cholinesterase Inhibitors ,Acetylcholine ,medicine.drug - Abstract
EVP-6124, (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, is a novel partial agonist of alpha 7 neuronal nicotinic acetylcholine receptors (nAChRs) that was evaluated here in vitro and in vivo. In binding and functional experiments, EVP-6124 showed selectivity for alpha 7 nAChRs and did not activate or inhibit heteromeric alpha 4 beta 2 nAChRs. EVP-6124 had good brain penetration and an adequate exposure time. EVP-6124 (0.3 mg/kg, p.o.) significantly restored memory function in scopolamine-treated rats (0.1 mg/kg, i.p.) in an object recognition task (ORT). Although donepezil at 0.1 mg/kg, p.o. or EVP-6124 at 0.03 mg/kg, p.o. did not improve memory in this task, co-administration of these sub-efficacious doses fully restored memory. In a natural forgetting test, an ORT with a 24 h retention time. EVP-6124 improved memory at 0.3 mg/kg, p.o. This improvement was blocked by the selective alpha 7 nAChR antagonist methyllycaconitine (0.3 mg/kg, i.p. or 10 mu g, i.c.v.). In co-application experiments of EVP-6124 with acetylcholine, sustained exposure to EVP-6124 in functional investigations in oocytes caused desensitization at concentrations greater than 3 nM, while lower concentrations (0.3-1 nM) caused an increase in the acetylcholine-evoked response. These actions were interpreted as representing a co-agonist activity of EVP-6124 with acetylcholine on alpha 7 nAChRs. The concentrations of EVP-6124 that resulted in physiological potentiation were consistent with the free drug concentrations in brain that improved memory performance in the ORT. These data suggest that the selective partial agonist EVP-6124 improves memory performance by potentiating the acetylcholine response of alpha 7 nAChRs and support new therapeutic strategies for the treatment of cognitive impairment. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
- Published
- 2012
18. Therapeutic strategies for Alzheimer's disease in clinical trials
- Author
-
Jakub Jończyk, Dawid Panek, Justyna Godyń, and Barbara Malawska
- Subjects
0301 basic medicine ,tau Proteins ,Idalopirdine ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,medicine ,Animals ,Humans ,Solanezumab ,Donepezil ,Encenicline ,Clinical Trials as Topic ,Amyloid beta-Peptides ,Memantine ,General Medicine ,medicine.disease ,030104 developmental biology ,Crenezumab ,Cholinesterase Inhibitors ,Alzheimer's disease ,Amyloid Precursor Protein Secretases ,Gantenerumab ,Psychology ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Alzheimer's disease (AD) is considered to be the most common cause of dementia and is an incurable, progressive neurodegenerative disorder. Current treatment of the disease, essentially symptomatic, is based on three cholinesterase inhibitors and memantine, affecting the glutamatergic system. Since 2003, no new drugs have been approved for treatment of AD. This article presents current directions in the search for novel, potentially effective agents for the treatment of AD, as well as selected promising treatment strategies. These include agents acting upon the beta-amyloid, such as vaccines, antibodies and inhibitors or modulators of γ- and β-secretase; agents directed against the tau protein as well as compounds acting as antagonists of neurotransmitter systems (serotoninergic 5-HT6 and histaminergic H3). Ongoing clinical trials with Aβ antibodies (solanezumab, gantenerumab, crenezumab) seem to be promising, while vaccines against the tau protein (AADvac1 and ACI-35) are now in early-stage trials. Interesting results have also been achieved in trials involving small molecules such as inhibitors of β-secretase (MK-8931, E2609), a combination of 5-HT6 antagonist (idalopirdine) with donepezil, inhibition of advanced glycation end product receptors by azeliragon or modulation of the acetylcholine response of α-7 nicotinic acetylcholine receptors by encenicline. Development of new effective drugs acting upon the central nervous system is usually a difficult and time-consuming process, and in the case of AD to-date clinical trials have had a very high failure rate. Most phase II clinical trials ending with a positive outcome do not succeed in phase III, often due to serious adverse effects or lack of therapeutic efficacy.
- Published
- 2015
19. Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication
- Author
-
George T. Grossberg, William James Deardorff, and Ahmad Shobassy
- Subjects
Oncology ,medicine.medical_specialty ,Quinuclidines ,medicine.drug_class ,Population ,Thiophenes ,Pharmacology ,Placebo ,Partial agonist ,Alzheimer Disease ,Internal medicine ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Nicotinic Agonists ,education ,Cholinesterase ,education.field_of_study ,Encenicline ,biology ,business.industry ,General Neuroscience ,Clinical trial ,Tolerability ,Acetylcholinesterase inhibitor ,Clinical Trials, Phase III as Topic ,biology.protein ,Neurology (clinical) ,Cholinesterase Inhibitors ,business - Abstract
Alzheimer's disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an α7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the α7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III trials under the title COGNITIV AD will assess the efficacy and tolerability of EVP-6124 in patients with mild-to-moderate AD. Based on the completed clinical trials and proposed mechanism of action, EVP-6124 would appear to be a good candidate for therapy in combination with cholinesterase inhibitors.
- Published
- 2014
20. Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains
- Author
-
Leslie Citrome
- Subjects
Bitopertin ,medicine.medical_specialty ,alpha7 Nicotinic Acetylcholine Receptor ,Glycine ,Bioinformatics ,Reuptake ,Dopamine ,mental disorders ,medicine ,Serine ,Humans ,Molecular Targeted Therapy ,Psychiatry ,Encenicline ,business.industry ,medicine.disease ,Psychiatry and Mental health ,Nicotinic acetylcholine receptor ,Receptors, Glutamate ,Schizophrenia ,NMDA receptor ,Reuptake inhibitor ,business ,Cognition Disorders ,medicine.drug ,Antipsychotic Agents - Abstract
Current treatments for schizophrenia, although effective for positive symptoms, have not proven as effective for negative symptoms and cognitive dysfunction. Additional strategies, such as combining antipsychotics or adding adjunctive agents to antipsychotics, have also yielded disappointing results in both negative and cognitive symptom domains. However, the N-methyl-d-aspartate (NMDA) receptor hypofunction hypothesis, with its focus on the glutamate system's effect on dopamine, can explain the positive, negative, and cognitive symptoms in schizophrenia. Therapeutic targets are being explored that focus on NMDA receptors (eg, glycine, d-serine), glycine reuptake inhibition (such as sarcosine and bitopertin), and, through a different pathway, α-7 nicotinic acetylcholine receptor agonism (eg, encenicline).
- Published
- 2014
21. P.3.b.015 Positive encenicline exposure-response relationships for cognition and clinical function in schizophrenia patients receiving atypical antipsychotics
- Author
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H. Kuan, Nancy Dgetluck, G. Loewen, and D. Hilt
- Subjects
Pharmacology ,medicine.medical_specialty ,Encenicline ,business.industry ,Cognition ,Exposure response relationships ,medicine.disease ,Psychiatry and Mental health ,Neurology ,Schizophrenia ,medicine ,Pharmacology (medical) ,Neurology (clinical) ,Psychiatry ,business ,Biological Psychiatry - Published
- 2015
22. Alpha-7 nicotinic agonist improves cognition in schizophrenia
- Author
-
Stephen R. Marder
- Subjects
Agonist ,050103 clinical psychology ,Encenicline ,medicine.drug_class ,05 social sciences ,Cognition ,Verbal learning ,Neuropsychopharmacology ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Nicotinic agonist ,Schizophrenia ,medicine ,Humans ,Verbal fluency test ,Original Article ,0501 psychology and cognitive sciences ,Nicotinic Agonists ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Acetylcholine ,medicine.drug - Abstract
Encenicline is a novel, selective α7 nicotinic acetylcholine receptor agonist in development for treating cognitive impairment in schizophrenia and Alzheimer's disease. A phase 2, double-blind, randomized, placebo-controlled, parallel-design, multinational study was conducted. Patients with schizophrenia on chronic stable atypical antipsychotics were randomized to encenicline 0.27 or 0.9 mg once daily or placebo for 12 weeks. The primary efficacy end point was the Overall Cognition Index (OCI) score from the CogState computerized battery. Secondary end points include MATRICS Consensus Cognitive Battery (MCCB) (in US patients), the Schizophrenia Cognition Rating Scale (SCoRS) total score, SCoRS global rating, and Positive and Negative Syndrome Scale (PANSS) total and subscale and cognition factor scores. Of 319 randomized patients, 317 were included in the safety population, and 307 were included in the intent-to-treat population. Notable trends in improvement were demonstrated across all cognition scales. For the OCI score, the LS mean difference for encenicline 0.27 mg vs placebo was significant (Cohen's d=0.257; P=0.034). Mean SCoRS total scores decreased showing improvement in function over time, and the difference was significant for encenicline 0.9 mg vs placebo (P=0.011). Furthermore, the difference between encenicline 0.9 mg and placebo was significant for the PANSS Cognition Impairment Domain (P=0.0098, Cohen's d=0.40) and for the PANSS Negative scale (P=0.028, Cohen's d=0.33). Treatment-emergent adverse events were reported at similar frequencies across all treatment groups (39.0% with placebo, 23.4% with encenicline 0.27 mg, and 33.3% with encenicline 0.9 mg). Overall, encenicline was generally well tolerated and demonstrated clinically meaningful improvements in cognition and function in patients with schizophrenia.
- Published
- 2016
23. Therapeutic improvements expected in the near future for schizophrenia and schizoaffective disorder: an appraisal of phase III clinical trials of schizophrenia-targeted therapies as found in US and EU clinical trial registries.
- Author
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Garay RP, Citrome L, Samalin L, Liu CC, Thomsen MS, Correll CU, Hameg A, and Llorca PM
- Subjects
- Clinical Trials, Phase III as Topic, Cognition Disorders drug therapy, European Union, Humans, Psychotic Disorders psychology, Registries, Schizophrenic Psychology, United States, Antipsychotic Agents therapeutic use, Psychotic Disorders drug therapy, Schizophrenia drug therapy
- Abstract
Introduction: In this review, the authors describe medications in phase III of clinical development for schizophrenia and schizoaffective disorder, and provide an opinion on how current treatment can be improved in the near future., Areas Covered: Recent (post 2013) phase III clinical trials of schizophrenia-targeted therapies were found in US and EU clinical trial registries. Two hundred fifty-three trials were identified, that included 16 investigational compounds. The antipsychotics brexpiprazole and cariprazine have been approved in the US, and although both are dopamine D2 receptor partial agonists, they differ markedly in their pharmacodynamic profiles. Encenicline and valbenazine are first-in-class candidates for treatment of cognitive impairment associated with schizophrenia (CIAS) and tardive dyskinesia, respectively. Eleven add-on compounds were previously approved for other therapeutic indications and are for the most part being studied at academic medical centers and smaller pharmaceutical companies for negative symptoms and CIAS or for specific populations (comorbidities, antipsychotic-induced obesity)., Expert Opinion: Promising new agents are emerging for schizophrenia and schizoaffective disorder. In addition to better-tolerated antipsychotics that treat positive symptoms, we could see the arrival of the first effective drug for negative symptoms and CIAS, which would strongly facilitate the ultimate goal of recovery in persons with schizophrenia.
- Published
- 2016
- Full Text
- View/download PDF
24. Tropisetron and its targets in Alzheimer's disease.
- Author
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Hashimoto K
- Subjects
- Alzheimer Disease drug therapy, Animals, Humans, Indoles therapeutic use, Inflammation metabolism, Nicotinic Agonists therapeutic use, Quinuclidines therapeutic use, Serotonin Antagonists therapeutic use, Thiophenes therapeutic use, Tropisetron, Alzheimer Disease metabolism, Indoles pharmacology, Nicotinic Agonists pharmacology, Serotonin Antagonists pharmacology, alpha7 Nicotinic Acetylcholine Receptor agonists
- Abstract
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Despite this, there are no drugs for preventing the onset of AD. Preclinical studies suggest that the interaction between amyloid-β peptides (Aβ) and the α7 nicotinic acetylcholine receptor (α7 nAChR) plays a key role in AD pathology, and that α7 nAChR agonists could act as potential therapeutic drugs for AD. A recent study demonstrated that tropisetron, a potent α7 nAChR agonist and serotonin 5-hydroxytryptamine3 receptor antagonist, also bound to the ectodomain of amyloid precursor protein. Furthermore, tropisetron promoted greater improvements in memory than current AD therapeutic drugs, such as memantine and donepezil. Positron emission tomography studies detected Aβ deposition and inflammation in the brains of subjects with amnestic mild cognitive impairment (MCI) before the onset of AD. Given the role of α7 nAChR in Aβ deposition and inflammation, tropisetron represents an attractive potential therapeutic drug to delay or prevent MCI and AD. Additionally as this drug is used internationally to treat chemotherapy-induced emesis, its safety record is already known.
- Published
- 2015
- Full Text
- View/download PDF
25. Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Encenicline, a Selective α7 Nicotinic Receptor Partial Agonist, in Single Ascending-dose and Bioavailability Studies
- Author
-
Monica Massaro, Andre van Vliet, Peter J. Snyder, Maria Gawryl, Dana Hilt, W Timmerman, Renger G. Tiessen, Nancy Dgetluck, Martijn Hilhorst, Ann J. Barbier, and Michael G. Palfreyman
- Subjects
Adult ,Male ,pharmacokinetic profile ,Quinuclidines ,Administration, Oral ,Biological Availability ,Capsules ,Thiophenes ,Bioequivalence ,Pharmacology ,Receptors, Nicotinic ,Partial agonist ,Food-Drug Interactions ,Cognition ,Sex Factors ,α7 nicotinic acetylcholine receptor agonist ,Pharmacokinetics ,Double-Blind Method ,pharmacodynamics ,Medicine ,Humans ,Pharmacology (medical) ,Nicotinic Agonists ,Encenicline ,Cross-Over Studies ,business.industry ,Fasting ,Crossover study ,Healthy Volunteers ,Bioavailability ,Tolerability ,Therapeutic Equivalency ,encenicline cognition ,Pharmacodynamics ,Female ,business ,bioavailability - Abstract
Purpose Encenicline (EVP-6124) is a selective α 7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer's disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers. Methods A single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers. Subjects received a single 1-, 3.5-, 7-, 20-, 60-, or 180-mg oral solution dose of encenicline or placebo. A second single-dose, randomized, open-label, 3-period, crossover study in healthy male and female subjects compared the relative bioavailability of a 1-mg oral capsule versus a 1-mg oral solution dose of encenicline and evaluated the effects of food and sex on encenicline pharmacokinetic profile. Findings In the first study, encenicline was well tolerated and dose-proportional increases in C max (mean range 0.59−100 ng/mL) and AUC 0−∞ (mean range 45.6−8890 ng·h/mL) were observed over a 1- to 180-mg dose range. Procognitive effects on the Digit Symbol Substitution Test were maximal at the 20-mg dose. In the second study, encenicline 1-mg oral capsules and oral solution were bioequivalent and there was no observed food effect on encenicline pharmacokinetic profile with the 90% confidence intervals of the treatment ratios for both comparisons (ie, capsule to solution and fed to fasted) for C max and AUC being within 80% to 125%. A 30% to 40% higher encenicline exposure in female subjects than respective values in male subjects was consistent with a 33% higher weight of the male subjects. No clinically relevant safety profile or tolerability effects of encenicline were observed. Implications Encenicline was well tolerated at single doses up to 180 mg, and doses as low as 1 mg had dose- and time-dependent pharmacodynamic effects on the central nervous system. Oral capsule and solution were bioequivalent and were not affected by food. Although a sex effect on pharmacokinetic profile was observed, it was attributable to weight differences. Clinical Trial Registration at EudraCT: 2006-005623-42 and EudracT: 2008-000029-20.
- Full Text
- View/download PDF
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