First-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Pirepemat, a Cortical Enhancer, in Healthy Volunteers.

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.

A first-in-human oral dose study of mesdopetam (IRL790) to assess its safety, tolerability, and pharmacokinetics in healthy male volunteers.

The management of Parkinson's 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.

Economic consequences of migraine in Sweden and implications for the cost-effectiveness of onabotulinumtoxinA (Botox) for chronic migraine in Sweden and Norway.

Background: Migraine is a common and incapacitating condition, with severe impact on the quality of life (QoL) of the afflicted and their families, and negative economic consequences through decreased workforce participation, reduced functional ability and elevated healthcare costs. This study aimed to describe the economic consequences of migraine in Sweden using cost of illness survey data and, based on this data, assess the cost-effectiveness of onabotulinumtoxinA (Botox) for the treatment of chronic migraine in Sweden and Norway.

Methods: A survey study was conducted in Swedish migraine patients, with questions on patient characteristics, headache frequency and severity, effect on daily activities and work, QoL, health resource utilization, and medication use.

(3)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent.

Here we describe for the first time the distinctive pharmacological profile for (3)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 µmol/kg, s.

Effects of a Novel Psychomotor Stabilizer, IRL790, on Biochemical Measures of Synaptic Markers and Neurotransmission.

The novel small-molecule psychomotor stabilizer, IRL790, is currently in clinical trial for treatment of levodopa-induced dyskinesia and psychosis in patients with Parkinson disease. Here, we used naïve mice to investigate the effects of acute systemic administration of IRL790 on protein levels and phosphorylation states of proteins relevant for synaptic plasticity and transmission. IRL790 increased pro-brain-derived neurotrophic factor protein levels and phosphorylation at Ser1303 of the N-methyl-D-aspartate (NMDA) subtype 2B glutamate receptor (NR2B) in prefrontal cortex.

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.

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.

A Phase 2a Trial Investigating the Safety and Tolerability of the Novel Cortical Enhancer IRL752 in Parkinson's Disease Dementia.

Background: IRL752 is a novel small-molecule compound that acts to regioselectively enhance norepinephrine, dopamine, and acetylcholine neurotransmission in the cerebral cortex.

Objective: The primary objective of the trial was to investigate the safety and tolerability of IRL752 in patients with Parkinson's disease and dementia.

Methods: Patients with Parkinson's disease and dementia were randomized to IRL752 or placebo treatment (3:1 ratio) for 28 days.

Safety and tolerability of IRL790 in Parkinson's disease with levodopa-induced dyskinesia-a phase 1b trial.

IRL790 is a novel compound with psychomotor stabilizing properties primarily targeting the dopamine D3 receptor. IRL790 is developed as an experimental treatment for levodopa-induced dyskinesia (LID), impulse control disorder, and psychosis in Parkinson's disease (PD). The primary objective was to investigate the safety and tolerability of IRL790 in PD patients with LID in a randomized controlled trial.

Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington's Disease.

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).

Antidopaminergic Medication is Associated with More Rapidly Progressive Huntington's Disease.

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.

The dopaminergic stabilizer pridopidine decreases expression of L-DOPA-induced locomotor sensitisation in the rat unilateral 6-OHDA model.

Treatment-limiting motor complications occur in patients with Parkinson's disease after chronic levodopa (L-DOPA) treatment, and represent an unmet medical need. We examined the motor and neurochemical effects of the dopaminergic stabilizer pridopidine (NeuroSearch A/S, Ballerup, Denmark) in the unilateral rodent 6-OHDA lesion model, which is often used to evaluate the potential of experimental compounds for such dopamine-related motor complications. In total, 72 rats were hemi-lesioned and allocated to receive twice-daily injections of either vehicle; 6.

Validation of the first quality-of-life measurement for patients with Huntington's disease: the Huntington Quality of Life Instrument.

Health-related quality-of-life instruments are critical for assessing disease burdens. Generic tools allow comparison between diseases but do not discriminate between disease severities. Specific tools also tend to be more sensitive.

The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans.

Purpose: The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians.

Methods: Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50 mg; PM, 25 mg).

Results: The mean total plasma clearance of pridopidine was 541 and 138 mL/min in EM and PM, respectively (p = 0.

Pridopidine for the treatment of motor function in patients with Huntington's disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial.

Background: Huntington's disease is a progressive neurodegenerative disorder, characterised by motor, cognitive, and behavioural deficits. Pridopidine belongs to a new class of compounds known as dopaminergic stabilisers, and results from a small phase 2 study in patients with Huntington's disease suggested that this drug might improve voluntary motor function. We aimed to assess further the effects of pridopidine in patients with Huntington's disease.

Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease.

Objectives: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment.

Extrastriatal dopamine D(2) receptor binding in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder, primarily affecting medium spiny neurones in the striatum. The density of striatal dopamine D(2) receptors is reduced in HD but there is little known about this biomarker in brain regions outside the striatum. The primary objective of this study was to compare extrastriatal dopamine D(2) receptor binding, in age-matched control subjects and patients with HD.

Efficacy and safety of the dopaminergic stabilizer Pridopidine (ACR16) in patients with Huntington's disease.

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).

Altered pattern of brain dopamine synthesis in male adolescents with attention deficit hyperactivity disorder.

Background: Limited data from positron emission tomography (PET) studies of subjects with attention-deficit/hyperactivity disorder (ADHD) indicate alterations in brain dopamine neurotransmission. However, these studies have used conventional univariate approaches that are less sensitive to detect complex interactions that may exist between different brain dopamine pathways and individual symptoms of ADHD. We aimed to investigate these potential interactions in adolescents with ADHD.

Different corticostriatal patterns of L-DOPA utilization in patients with untreated schizophrenia and patients treated with classical antipsychotics or clozapine.

Positron emission tomography (PET) has been shown to be of great importance in elucidating the mechanism of action of antipsychotic drugs. In psychotic patients L-[11C]DOPA PET has been used to demonstrate some differences in dopaminergic activity compared with that in healthy volunteers. Ten healthy volunteers were investigated with PET and L-[11C]DOPA.

PNU-96391A (OSU6162) antagonizes the development of behavioral sensitization induced by dopamine agonists in a rat model for Parkinson's disease.

PNU-96391A is a weak dopamine (DA) D(2) receptor antagonist with behavioral stabilizing properties. Previous experiments revealed that PNU-96391A antagonizes the expression of L-DOPA induced behavioral sensitization (dyskinesias) in lesioned primates without inducing akinesia or reducing the anti-Parkinsonian efficacy of L-DOPA. This study evaluated the ability of PNU-96391A to block the development of DA agonist-induced behavioral sensitization in rats with unilateral 6-OH-DA lesions of the median forebrain bundle.

Coadministration of (-)-OSU6162 with l-DOPA normalizes preproenkephalin mRNA expression in the sensorimotor striatum of primates with unilateral 6-OHDA lesions.

The substituted phenylpiperidine (-)-OSU6162 is a novel modulator of the dopaminergic systems with low affinity for dopamine D(2) receptors and potent normalizing effects on l-DOPA-induced dyskinesias. We studied the effects of coadministration of (-)-OSU6162 with l-DOPA on the regulation of striatal preproenkephalin (PPE) and prodynorphin (PDyn) mRNA expression in the primate brain by in situ hybridization histochemistry. Common marmoset monkeys sustaining unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway received l-DOPA/carbidopa, l-DOPA/carbidopa plus (-)-OSU6162, or vehicle over 14 days.

Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence.

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.

Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand on L-DOPA-induced dyskinesias in MPTP monkeys.

(S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine ((-)-OSU6162) is a phenylpiperidine derivative which exhibits low affinity to the dopamine D2 receptor in vitro. However, in vivo, positron emission tomography scanning studies show that the compound displaces the selective dopamine D2 receptor antagonist, raclopride. We have evaluated, in this study, the effect of (-)-OSU6162, on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a primate model of Parkinson's disease.

Motor effects of (-)-OSU6162 in primates with unilateral 6-hydroxydopamine lesions.

The effects of the novel compound, (-)-OSU6162 ((S)-(-)-3-methylsulfonylphenyl-1-propylpiperidine), on rotational behavior induced by dopamine receptor agonists was investigated in common marmosets (Callithrix jacchus) with unilateral 6-hydroxydopamine lesions. (-)-OSU6162 per se displayed no effect on the animals' behavior. On the other hand, pretreatment with (-)-OSU6162 attenuated rotational behavior induced by apomorphine (apomorphini hydrochloridum), L-DOPA (3,4-dihydroxyphenylalanine), and the dopamine D2 receptor agonist, quinpirole (trans-(-)-4aR-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolol[3,4-g]quinoline hydrochloride), without inducing motor impairment such as akinesia or dystonia.