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- Holm-Waters, Susanna, et al.
(författare)
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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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Ingår i: 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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Tidskriftsartikel (refereegranskat)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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- Lundin, Anders, et al.
(författare)
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Efficacy and Safety of the Dopaminergic Stabilizer Pridopidine (ACR16) in Patients With Huntington's Disease
- 2010
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Ingår i: Clinical neuropharmacology. - 0362-5664 .- 1537-162X. ; 33:5, s. 260-264
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Tidskriftsartikel (refereegranskat)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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- Nilsson, Dag, et al.
(författare)
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Absorption of L-DOPA from the proximal small intestine studied in the rhesus monkey by positron emission tomography
- 1999
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Ingår i: European Journal of Pharmaceutical Sciences. - 0928-0987 .- 1879-0720. ; 7:3, s. 185-189
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Tidskriftsartikel (refereegranskat)abstract
- Positron emission tomography (PET) seems to be a valuable method for the understanding of intestinal absorption mechanisms, for simultaneous quantitation of absorption rate and distribution kinetics to the tissues of interest after oral drug delivery. PET was evaluated in three Rhesus monkeys for quantitation of the absorption rate from the gastrointestinal tract and the distribution kinetics into different organs. To obtain optimal standardized conditions for the measurement of absorption the drug was administered via a naso-duodenal catheter directly to the absorption site in the proximal small intestine. l-DOPA was used as study drug given in a suspension together with carbidopa and the radiomarker l-[beta-11C]DOPA. The l-DOPA suspension was given into the duodenum without and after administration of a suspension of six l-amino acids (120 mM) in order to investigate any interaction on the intestinal absorption and distribution of l-DOPA into the liver and brain tissue. Intestinal absorption was in general minor during the first study period and higher together with administered l-amino acids. The somewhat contradictory result with increased absorption when amino acids were present in the intestinal lumen, may be a consequence of increased intestinal motility initiated by the nutrient load.
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- Rein-Hedin, Erik, et al.
(författare)
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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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Ingår i: Clinical Pharmacology in Drug Development. - : John Wiley & Sons. - 2160-763X .- 2160-7648. ; 10:12, s. 1485-1494
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Tidskriftsartikel (refereegranskat)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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- Sjöberg, Folke, et al.
(författare)
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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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Ingår i: Pharmacology Research & Perspectives. - : Wiley. - 2052-1707. ; 9:3
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Tidskriftsartikel (refereegranskat)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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- Tedroff, Joakim, et al.
(författare)
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Antidopaminergic Medication is Associated with More Rapidly Progressive Huntington's Disease
- 2015
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Ingår i: Journal of Huntington's Disease. - 1879-6397 .- 1879-6400. ; 4:2, s. 131-140
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Tidskriftsartikel (refereegranskat)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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