| 1. |
- Carlsson, Arvid, 1923, et al.
(author)
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Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence
- 2001
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In: Annu Rev Pharmacol Toxicol. - 0362-1642. ; 41, s. 237-60
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Research review (peer-reviewed)abstract
- In spite of its proven heuristic value, the dopamine hypothesis of schizophrenia is now yielding to a multifactorial view, in which the other monoamines as well as glutamate and GABA are included, with a focus on neurotransmitter interactions in complex neurocircuits. The primary lesion(s) in schizophrenia does not necessarily involve any of these neurotransmitters directly but could deal with a more general defect, such as a faulty connectivity of developmental origin. Nevertheless, a precise identification of neurotransmitter aberrations in schizophrenia will probably provide clues for a better understanding of the disease and for the development of new treatment and prevention strategies.
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| 2. |
- Carlsson, Maria L., 1959, et al.
(author)
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The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice
- 1999
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In: J Neural Transm. - 0300-9564. ; 106:2, s. 123-9
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Journal article (peer-reviewed)abstract
- The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.
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| 3. |
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| 4. |
- Holm-Waters, Susanna, et al.
(author)
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Preclinical Pharmacology of 2-(3-Fluoro-5-Methanesulfonyl-phenoxy)Ethyl (Propyl)amine (IRL790), a Novel Dopamine Transmission Modulator for the Treatment of Motor and Psychiatric Complications in Parkinson Disease
- 2020
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In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 374:1, s. 113-125
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Journal article (peer-reviewed)abstract
- IRL790 ([2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, mesdopetam) is a novel compound in development for the clinical management of motor and psychiatric disabilities in Parkinson disease. The discovery of IRL790 was made applying a systems pharmacology approach based on in vivo response profiling. The chemical design idea was to develop a new type of DA D3/D2 receptor type antagonist built on agonist rather than antagonist structural motifs. We hypothesized that such a dopamine antagonist with physicochemical properties similar to agonists would exert antidyskinetic and antipsychotic effects in states of dysregulated dopaminergic signaling while having little negative impact on physiologic dopamine transmission and, hence, minimal liability for side effects related to dopamine-dependent functions. At the level of in vivo pharmacology, IRL790 displays balancing effects on aberrant motor phenotypes, reducing L-DOPA-induced dyskinesias in the rodent 6-hydroxydopamine lesion model and reducing psychostimulant-induced locomotor hyperactivity elicited by pretreatment with either d-amphetamine or dizocilpine, without negatively impacting normal motor performance. Thus, IRL790 has the ability to normalize the behavioral phenotype in hyperdopaminergic as well as hypoglutamatergic states. Neurochemical and immediate early gene (IEG) response profiles suggest modulation of DA neurotransmission, with some features, such as increased DA metabolites and extracellular DA, shared by atypical antipsychotics and others, such as increased frontal cortex IEGs, unique to IRL790. IRL790 also increases extracellular levels of acetylcholine in the prefrontal cortex and ventral hippocampus. At the receptor level, IRL790 appears to act as a preferential DA D3 receptor antagonist. Computational docking studies support preferential affinity at D3 receptors with an agonist-like binding mode. SIGNIFICANCE STATEMENT This paper reports preclinical pharmacology along with molecular modeling results on IRL790, a novel compound in clinical development for the treatment of motor and psychiatric complications in advanced Parkinson disease. IRL790 is active in models of perturbed dopaminergic and glutamatergic signaling, including rodent 6-hydroxydopamine L-DOPA-induced dyskinesias and psychostimulant-induced hyperactivity, in a dose range that does not impair normal behavior. This effect profile is attributed to interactions at dopamine D2/D3 receptors, with a 6- to 8-fold preference for the D3 subtype.
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| 5. |
- Lundin, Anders, et al.
(author)
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Efficacy and Safety of the Dopaminergic Stabilizer Pridopidine (ACR16) in Patients With Huntington's Disease
- 2010
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In: Clinical neuropharmacology. - 0362-5664 .- 1537-162X. ; 33:5, s. 260-264
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Journal article (peer-reviewed)abstract
- Objectives: To evaluate the efficacy and safety of the dopaminergic stabilizer pridopidine (ACR16) in patients with Huntington's disease (HD). Methods: In a randomized, double-blind, placebo-controlled, 4-week trial, patients with HD received pridopidine (50 mg/d, n = 28) or placebo (n = 30). The primary outcome measure was the change from baseline in weighted cognitive score, assessed by cognitive tests (Symbol Digit Modalities, verbal fluency, and Stroop tests). Secondary outcome measures included changes in the Unified Huntington's Disease Rating Scale, Hospital Anxiety and Depression Scale, Leeds Sleep Evaluation Questionnaire, Reitan Trail-Making Test A, and Clinical Global Impression of Change. Safety assessments were also performed. Results: There was no significant difference between pridopidine and placebo in the change from baseline of the weighted cognitive score. However, secondary measures such as affective symptoms showed trends toward improvement, and there was significant improvement in voluntary motor symptoms compared with placebo (P<0.05). Pridopidine was well tolerated, with a safety profile similar to placebo. Conclusions: Pridopidine shows promise as a treatment for some of the symptoms of HD. In this small-scale study, the most notable effect was improvement in voluntary motor symptoms. Larger, longer-term trials are warranted.
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| 6. |
- Rein-Hedin, Erik, et al.
(author)
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First-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Pirepemat, a Cortical Enhancer, in Healthy Volunteers
- 2021
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In: Clinical Pharmacology in Drug Development. - : John Wiley & Sons. - 2160-763X .- 2160-7648. ; 10:12, s. 1485-1494
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Journal article (peer-reviewed)abstract
- Pirepemat (IRL752) is a cortical enhancer being developed for the prevention of falls in patients with Parkinson disease. This first-in-human, randomized, double-blind, placebo-controlled phase 1 study evaluated safety, tolerability, and pharmacokinetics (PK) of pirepemat administered as oral single ascending doses (10, 35, 75, 175, 350 mg) and multiple ascending doses (100 and 250 mg 3 times daily) for 7 days to healthy male volunteers. Twenty and 24 subjects were randomly assigned in the single ascending dose and multiple ascending doses parts of the study, respectively. Pirepemat was generally well tolerated, although an increased frequency of adverse events of mild intensity within nervous system disorders (headache and dizziness) was seen after administration of 350 mg as a single dose and after multiple doses of 100 and 250 mg. PK of pirepemat showed a linear relationship over the dose range studied and exhibited dose proportionality after multiple-dose administration. Accumulation after 7 days of multiple dosing was minor. Absorption was rapid, with a median time to maximum concentration of 2.0 hours on day 1 and day 7 (100 and 250 mg) and a mean terminal half-life between 3.7 and 5.2 hours. Food intake had no (obvious) impact on PK. The results support 3-times-daily dosing and further clinical development.
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| 7. |
- Sjöberg, Folke, et al.
(author)
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A first-in-human oral dose study of mesdopetam (IRL790) to assess its safety, tolerability, and pharmacokinetics in healthy male volunteers
- 2021
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In: Pharmacology Research & Perspectives. - : Wiley. - 2052-1707. ; 9:3
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Journal article (peer-reviewed)abstract
- The management of Parkinsons disease (PD) is frequently compromised by complications induced by dopaminergic treatment such as involuntary movements (dyskinesias) and psychosis. Mesdopetam (IRL790) is a novel dopamine D3 receptor antagonist developed for the management of complications of therapy in PD. This study evaluated the safety, tolerability, and pharmacokinetics of escalating single and multiple doses of mesdopetam. We conducted a prospective, single-center, randomized, double-blind, placebo-controlled phase I, and first-in-human (FIH) study with mesdopetam administered to healthy male subjects. Overall, mesdopetam was well-tolerated up to a 120 mg single dose and up to 80 mg upon multiple dosing. Adverse events (AEs) were mainly related to the nervous system and were dose-dependent. No serious adverse events occurred and no AEs led to withdrawal. The results of the single-ascending-dose and multiple-ascending-dose parts indicated dose- and time-independent pharmacokinetics with rapid absorption and maximum plasma levels that were generally reached within 2 h after dosing. No accumulation was observed upon multiple dosing. It is concluded that mesdopetam was safe and well-tolerated in healthy male volunteers. Pharmacokinetic analysis indicated rapid absorption and dose-linear pharmacokinetics of mesdopetam, with a plasma half-life of around 7 h, upon single and repeated dosing. The pharmacokinetics of mesdopetam supports twice-daily use in patients.
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| 8. |
- Waters, Susanna, et al.
(author)
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Co-administration of the dopaminergic stabilizer pridopidine and tetrabenazine in rats
- 2014
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In: Journal of Huntington's Disease. - 1879-6397 .- 1879-6400. ; 3:3, s. 285-298
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Journal article (peer-reviewed)abstract
- Background: The efficacy of the dopaminergic stabilizer, pridopidine, in reducing the voluntary and involuntary motor symptoms of Huntington's disease (HD) is under clinical evaluation. Tetrabenazine is currently the only approved treatment for chorea, an involuntary motor symptom of HD; both compounds influence monoaminergic neurotransmission. Objective: To investigate pharmacological interactions between pridopidine and tetrabenazine. Methods: Drug-interaction experiments, supplemented by dose-response data, examined the effects of these compounds on locomotor activity, on striatal levels of dopamine and 3,4 - dihydroxyphenylacetic acid (DOPAC), and on levels of activity-regulated cytoskeleton-associated (Arc) gene expression in the striatum and frontal cortex of male Sprague-Dawley rats. Haloperidol, a classical dopamine D2 receptor antagonist, was also tested for comparison. Results: Monitoring for 1 hour after co-administration of tetrabenazine 0.64 mg/kg and pridopidine 32 mg/kg revealed a reduction in locomotor activity, measured as distance travelled, in the tetrabenazine treated group, down to 61% vs. vehicle controls (p < 0.001). This was significantly alleviated by pridopidine (distance travelled reached 137% vs. tetrabenazine controls, p < 0.01). In contrast, co-administration of haloperidol 0.12 mg/kg and tetrabenazine produced increased inhibition of locomotor activity over the same period (p < 0.01, 41% vs. tetrabenazine). Co-administration of pridopidine, 10.5 mg/kg or 32 mg/kg, with tetrabenazine counteracted significantly (p < 0.05) and dose-dependently the decrease in frontal cortex Arc levels induced by tetrabenazine 0.64 mg/kg (Arc mRNA reached 193% vs. tetrabenazine mean at 32 mg/kg); this counteraction was not seen with haloperidol. Tetrabenazine retained its characteristic neurochemical effects of increased striatal DOPAC and reduced striatal dopamine when co-administered with pridopidine. Conclusions: Pridopidine alleviates tetrabenazine-induced behavioural inhibition in rats. This effect may be associated with pridopidine-induced changes in cortical activity and may justify clinical evaluation of pridopidine/tetrabenazine combination therapy.
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| 9. |
- Waters, Susanna, et al.
(author)
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In Vivo Systems Response Profiling and Multivariate Classification of CNS Active Compounds: A Structured Tool for CNS Drug Discovery
- 2017
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In: Acs Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 8:4, s. 785-797
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Journal article (peer-reviewed)abstract
- This paper describes the application of in vivo systems response profiling in CNS drug discovery by a process referred to as the Integrative Screening Process. The biological response profile, treated as an array, is used as major outcome for selection of candidate drugs. Dose response data, including ex vivo brain monoaminergic biomarkers and behavioral descriptors, are systematically collected and analyzed by principal component analysis (PCA) and partial least-squares (PLS) regression, yielding multivariate characterization across compounds. The approach is exemplified by assessing a new class of CNS active compounds, the dopidines, compared to other monoamine modulating compounds including antipsychotics, antidepressants, and procognitive agents. Dopidines display a distinct phenotypic profile which has prompted extensive further preclinical and clinical investigations. In summary, in vivo profiles of CNS compounds are mapped, based on dose response studies in the rat. Applying a systematic and standardized work-flow, a database of in vivo systems response profiles is compiled, enabling comparisons and classification. This creates a framework for translational mapping, a crucial component in CNS drug discovery.
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| 10. |
- Waters, Susanna, et al.
(author)
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Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington's Disease
- 2018
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In: Journal of Huntingtons Disease. - : IOS Press. - 1879-6397 .- 1879-6400. ; 7:1, s. 1-16
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Research review (peer-reviewed)abstract
- Despite advances in understanding the pathophysiology of Huntington's disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect. This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD.
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| 11. |
- Waters, Susanna, et al.
(author)
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The dopaminergic stabilizers pridopidine and ordopidine enhance cortico-striatal Arc gene expression
- 2014
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In: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 121:11, s. 1337-1347
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Journal article (peer-reviewed)abstract
- The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3-(methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D-2 receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc), an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D-1 and D-2 receptor agonists and antagonists, as well as the partial dopamine D-2 agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D-1 and D-2 compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D-2 receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4-dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D-2 receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-d-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine.
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| 12. |
- Gondalia, Jagdish Shivlal, 1959, et al.
(author)
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Relationships between free radical levels during carotid endarterectomy and markers of arteriosclerotic disease
- 2007
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In: Int J Med Sci. - 1449-1907. ; 14:3, s. 124-130
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Journal article (peer-reviewed)abstract
- Background: Free radical production is elevated in jugular venous blood emerging from the brain in conjunction with carotid endarterectomy. This study explores the relationships between markers for lesion progression in arteriosclerosis, production of radicals and clinical characteristics. Methods: The radical production during carotid endarterectomy was studied in 13 patients with an ex vivo spin trap method using OXANOH as a spin trap. MCP-1, ICAM-1, MMP-9 and oxLDL were determined in venous blood samples before, during and after clamping of the carotid artery. Principal component analysis (PCA) as well as partial least square regression analysis (PLS) was applied to interpret the data. Results: PCA and PLS analysis revealed that high values of MMP-9 and low values of ICAM-1 were associated with high radical production whereas MCP-1 and oxLDL were not correlated to radical production. MMP-9 was elevated at diabetes, high haemoglobin, high leucocyte counts and thrombocyte counts as well as at contralateral stenosis, whereas ICAM-1 showed reversed relationships to these clinical variables. MCP-1 increased during surgery. Conclusions: The main finding in our study is that MMP-9 in plasma is asscociated with radical production during carotid endarterectomy, suggesting that this enzyme might be involved in the pathogenesis of brain damage in conjunction with ischaemia-reperfusion.
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| 13. |
- Stan, Tiberiu Loredan, et al.
(author)
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Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis
- 2024
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In: Neurotherapeutics. - : Elsevier. - 1878-7479 .- 1933-7213. ; 21:2, s. 1-12
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Journal article (peer-reviewed)abstract
- Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.
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| 14. |
- Tedroff, Joakim, et al.
(author)
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Antidopaminergic Medication is Associated with More Rapidly Progressive Huntington's Disease
- 2015
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In: Journal of Huntington's Disease. - 1879-6397 .- 1879-6400. ; 4:2, s. 131-140
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Journal article (peer-reviewed)abstract
- Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder leading to progressive motor, cognitive and functional decline. Antidopaminergic medications (ADMs) are frequently used to treat chorea and behavioural disturbances in HD. Objective: We aimed to assess how the use of such medications was associated with the severity and progression of the motor aspects of the condition, given that there have been concerns that such drugs may actually promote neurological deterioration. Methods: Using multiple linear regression, supplemented by principal component analysis to explore the overall correlation patterns and help identify relevant covariates, we assessed severity and progression of motor symptoms and functional decline in 651 manifest patients from the REGISTRY cohort followed for two years. ADM treated versus non-treated subjects were compared with respect to motor impairment at baseline and progression rate by means of multiple regression, adjusting for CAG-repeat and age. Results: Patients treated with ADMs had significantly worse motor scores with greater functional disability at their first visit. They also showed a higher annual rate of progression of motor signs and disability over the next two years. In particular the rate of progression for oculomotor symptoms and bradykinesia was markedly increased whereas the rate of progression of chorea and dystonia was similar for ADM and drug nai¨ve patients. These differences in clinical severity and progression could not be explained by differences in disease burden, duration of disease or other possible prognostic factors. Conclusions: The results from this analysis suggest ADM treatment is associated with more advanced and rapidly progressing HD although whether these drugs are causative in driving this progression requires further, prospective studies. © 2015 - IOS Press and the authors. All rights reserved.
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