Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis.

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.

Long-term incidence of haematological cancer after bariatric surgery or usual care in the Swedish Obese Subjects study: a prospective cohort study.

Background: Bariatric surgery in people with obesity is associated with a reduced overall cancer risk. Retrospective studies indicate that bariatric surgery specifically might reduce the risk of haematological cancers, but there is an absence of data from long-term, prospective studies. We therefore studied the association between bariatric surgery and haematological cancer in the Swedish Obese Subjects study.

Successful switching from risperidone to cariprazine in a schizophrenic patient with pronounced functional deficit. Case report.

A 22-year-old male was admitted to an in-patient psychiatric unit for treatment, after a period of 2 years of increasing psychotic symptoms corresponding to a very severe case of schizophrenia across the entire scale of symptom disorder domains along with some drug abuse comorbidity. Previous treatments with olanzapine (OLA) and risperidone (RIS) had been at best partly successful toward his positive symptoms with no, or even worsening effects on the negative symptomatology. Given the gravity of the latter symptoms and functional impairment of our patient, he might thus have been a candidate for clozapine (CLZ) treatment.

Turn On, Tune In, Turnover! Target Biology Impacts In Vivo Potency, Efficacy, and Clearance.

Even though significant efforts have been spent in recent years to understand and define the determinants of in vivo potency and clearance, important pieces of information are still lacking. By introducing target turnover into the reasoning, we open up to further the understanding of central factors important to the optimization of translational dose-concentration-response predictions. We describe (i) new (open model) expressions of the in vivo potency and efficacy parameters, which embody target turnover, binding, and complex kinetics, also capturing full, partial, and inverse agonism and antagonism; (ii) a detailed examination of open models to show what potency and efficacy parameters have in common and how they differ; and (iii) a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease state, hormonal and nutritional state, and day-night cycle.

Remission of Persistent Negative Symptoms and Psychosocial Consequences by Combined Clozapine and Cariprazine Treatment in a Patient With Long-Standing Treatment-Resistant Schizoaffective Disorder.

This patient case report describes a 45-year old white unmarried man with disability pension due to schizoaffective disorder, diagnosed at the age of 24. He lives in an apartment and has housing support. Retrospectively, the patient displayed prodromal markers of a disorder within the schizophrenia spectrum many years before the onset of frank psychosis, indeed since childhood.

The More, the Merrier…? Antipsychotic Polypharmacy Treatment Strategies in Schizophrenia From a Pharmacology Perspective.

Antipsychotic polypharmacy/drug combination treatment (APP) is a remarkably common practice in the schizophrenia context, given the lack of general support in treatment Guidelines. There is also a vast literature on APP outcomes, but a paucity of high-quality evidence-based data to guide and optimize adequate use of APP. This seems particularly true regarding many pharmacology-based considerations involved in APP treatment strategies.

Case Report: Cariprazine in a Patient With Schizophrenia, Substance Abuse, and Cognitive Dysfunction.

This case report describes a 30-year old male diagnosed with schizophrenia at the age of 23, and with a long history of drug abuse. He had previously received a wide range of antipsychotic drug treatment regimens, all with some degree of effect, but never with complete symptom relief. He was also suffering from persistent cognitive and negative symptoms.

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.

Does In Vitro Potency Predict Clinically Efficacious Concentrations?

The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n = 164) and how they may differ depending on therapeutic indication, mode of action, receptor type, target localization, and function. Approximately 70% of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median ratio of exposure in relation to in vitro potency was 0.

Reoperations After Bariatric Surgery in 26 Years of Follow-up of the Swedish Obese Subjects Study.

Importance: Bariatric surgery is an established treatment for obesity, but knowledge on the long-term incidence of revisional surgery is scarce.

Objective: To determine the incidence and type of revisional surgery after bariatric surgery in 26 years of follow-up of participants in the Swedish Obese Subjects (SOS) study.

Design, Setting, And Participants: The SOS study is a prospective nonrandomized controlled study comparing bariatric surgery (banding, vertical banded gastroplasty [VBG], and gastric bypass [GBP]) with usual care.

Dose-Response-Time Data Analysis: An Underexploited Trinity.

The most common approach to in vivo pharmacokinetic and pharmacodynamic analyses involves sequential analysis of the plasma concentration and responsetime data, such that the plasma kinetic model provides an independent function, driving the dynamics. However, in situations when plasma sampling may jeopardize the effect measurements or is scarce, nonexistent, or unlinked to the effect (e.g.

Lost in translation: What's in an EC? Innovative PK/PD reasoning in the drug development context.

Translation across species and from in vitro to in vivo is a central tenet in drug discovery pharmacology. Successful implementation requires proper assessment of both in vivo potency and efficacy. This notwithstanding, in vivo data is typically defined mostly in terms of ligand-to-target binding affinity, similar to in vitro studies.

Long-term incidence of serious fall-related injuries after bariatric surgery in Swedish obese subjects.

Obesity increases risk of falling, but the effect of bariatric surgery on fall-related injuries is unknown. The aim of this study was therefore to study the association between bariatric surgery and long-term incidence of fall-related injuries in the prospective, controlled Swedish Obese Subjects study. At inclusion, body mass index was ≥ 34 kg/m in men and ≥38 kg/m in women.

In vivo potency revisited - Keep the target in sight.

Potency is a central parameter in pharmacological and biochemical sciences, as well as in drug discovery and development endeavors. It is however typically defined in terms only of ligand to target binding affinity also in in vivo experimentation, thus in a manner analogous to in in vitro studies. As in vivo potency is in fact a conglomerate of events involving ligand, target, and target-ligand complex processes, overlooking some of the fundamental differences between in vivo and in vitro may result in serious mispredictions of in vivo efficacious dose and exposure.

Long-term incidence of microvascular disease after bariatric surgery or usual care in patients with obesity, stratified by baseline glycaemic status: a post-hoc analysis of participants from the Swedish Obese Subjects study.

Background: Bariatric surgery is associated with remission of diabetes and prevention of diabetic complications in patients with obesity and type 2 diabetes. Long-term effects of bariatric surgery on microvascular complications in patients with prediabetes are unknown. The aim of this study was to examine the effects of bariatric surgery on incidence of microvascular complications in patients with obesity stratified by baseline glycaemic status.

Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain.

Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin.

Deletion of Gpr55 Results in Subtle Effects on Energy Metabolism, Motor Activity and Thermal Pain Sensation.

The G-protein coupled receptor 55 (GPR55) is activated by cannabinoids and non-cannabinoid molecules and has been speculated to play a modulatory role in a large variety of physiological and pathological processes, including in metabolically perturbed states. We therefore generated male mice deficient in the gene coding for the cannabinoid/lysophosphatidylinositol (LPI) receptor Gpr55 and characterized them under normal dietary conditions as well as during high energy dense diet feeding followed by challenge with the CB1 receptor antagonist/GPR55 agonist rimonabant. Gpr55 deficient male mice (Gpr55 KO) were phenotypically indistinguishable from their wild type (WT) siblings for the most part.

Looking back (and in)to the future: A personal reflection on 'Serotonin autoreceptor function and antidepressant drug action' (Hjorth et al., 2000).

Our article in this journal some 15 years ago focussed on the role of serotonin (5-HT) autoreceptors in the mechanism of action of antidepressant drugs. Specifically in this regard, the results were summarised of rat microdialysis studies carried out to examine: (a) the relative importance of 5-HT and 5-HT autoreceptors, including (b) possible regional variation, and (c) potential changes in autoreceptor responsiveness following chronic selective serotonin reuptake inhibitor administration. In the present reflection piece, I recap some of the key findings against a brief background and provide an account of their bearing within the context of subsequent endeavours in the antidepressant drug research and development field.

Pattern Recognition in Pharmacodynamic Data Analysis.

Pattern recognition is a key element in pharmacodynamic analyses as a first step to identify drug action and selection of a pharmacodynamic model. The essence of this process is going from data to insight through exploratory data analysis. There are few formal strategies that scientists typically use when the experiment has been done and data collected.

Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach.

The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist).

A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.

There is a medical need for safe and efficacious anti-obesity drugs with acceptable side effect profiles. To mitigate the challenge posed by translating target interaction across species and balancing beneficial vs. adverse effects, a positron emission tomography (PET) approach could help guide clinical dose optimization.

Baseline anandamide levels and body weight impact the weight loss effect of CB1 receptor antagonism in male rats.

The individual weight loss response to obesity treatment is diverse. Here we test the hypothesis that the weight loss response to the CB1 receptor antagonist rimonabant is influenced by endogenous levels of receptor agonists. We show that baseline anandamide levels and body weight independently contribute to predict the treatment response to rimonabant in rodents, demonstrating that addition of biomarkers related to mode of action is relevant for a personalized health care approach to obesity treatment.

Modeling and design of challenge tests: Inflammatory and metabolic biomarker study examples.

Given the complexity of pharmacological challenge experiments, it is perhaps not surprising that design and analysis, and in turn interpretation and communication of results from a quantitative point of view, is often suboptimal. Here we report an inventory of common designs sampled from anti-inflammatory, respiratory and metabolic disease drug discovery studies, all of which are based on animal models of disease involving pharmacological and/or patho/physiological interaction challenges. The corresponding data are modeled and analyzed quantitatively, the merits of the respective approach discussed and inferences made with respect to future design improvements.

Modeling energy intake by adding homeostatic feedback and drug intervention.

Energy intake (EI) is a pivotal biomarker used in quantification approaches to metabolic disease processes such as obesity, diabetes, and growth disorders. Eating behavior is however under both short-term and long-term control. This control system manifests itself as tolerance and rebound phenomena in EI, when challenged by drug treatment or diet restriction.