Inhibition of follicle-stimulating hormone-induced preovulatory follicles in rats treated with a nonsteroidal negative allosteric modulator of follicle-stimulating hormone receptor.

We previously described a negative allosteric modulator (NAM) of FSHR (ADX61623) that blocked FSH-induced cAMP and progesterone production but did not block estradiol production. That FSHR NAM did not affect FSH-induced preovulatory follicle development as evidenced by the lack of an effect on the number of FSH-dependent oocytes found in the ampullae following ovulation with hCG. A goal is the development of a nonsteroidal contraceptive.

ADX71441, a novel, potent and selective positive allosteric modulator of the GABA(B) receptor, shows efficacy in rodent models of overactive bladder.

Background And Purpose: The GABAB receptor agonist baclofen reduces urethral resistance and detrusor overactivity in patients with spasticity. However, baclofen's side effects limit its use for the treatment of overactive bladder (OAB). Here, we tested a novel GABAB positive allosteric modulator (PAM) ADX71441 in models of OAB in mice and guinea pigs.

The Ventricular-Arterial Coupling: From Basic Pathophysiology to Clinical Application in the Echocardiography Laboratory.

The interplay between cardiac function and arterial system, which in turn affects ventricular performance, is defined commonly ventricular-arterial coupling and is an expression of global cardiovascular efficiency. This relation can be expressed in mathematical terms as the ratio between arterial elastance (EA) and end-systolic elastance (EES) of the left ventricle (LV). The noninvasive calculation requires complicated formulae, which can be, however, easily implemented in computerized algorithms, allowing the adoption of this index in the clinical evaluation of patients.

Safety evaluation of nasopharyngeal cooling (RhinoChill®) in stroke patients: an observational study.

Introduction: New technologies for therapeutic cooling have become available. The objective of our study was to investigate the safety of nasopharyngeal cooling with the RhinoChill(®) device in stroke patients, focusing on systemic and neurovital parameters.

Methods: In this prospective observational study, consecutive patients with severe ischemic or hemorrhagic stroke who underwent intracranial pressure (ICP) and brain temperature monitoring have been enrolled.

Reduction of excessive alcohol drinking by a novel GABAB receptor positive allosteric modulator ADX71441 in mice.

Rationale: A promising pharmacotherapy for alcohol use disorders has been positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB R) since GABAB R PAMs reduce ethanol drinking and self-administration in rodents.

Objective: The current studies investigated a novel, selective GABAB R PAM, ADX71441, in comparison to naltrexone in a protocol of ethanol binge-like drinking, drinking-in-the-dark (DID), and in a model of long-term, excessive drinking, intermittent access to ethanol (IA).

Methods: Male C57BL/6 J mice were given doses of ADX71441 (3, 10, 30 mg/kg, p.

A novel series of metabotropic glutamate receptor 5 negative allosteric modulators based on a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine core.

A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established.

Induction of cooling with a passive head and neck cooling device: effects on brain temperature after stroke.

Background And Purpose: Therapeutic hypothermia improves clinical outcome after cardiac arrest and appears beneficial in other cerebrovascular diseases. We conducted this study to investigate the relationship between surface head/neck cooling and brain temperature.

Methods: Prospective observational study enrolling consecutive patients with severe ischemic or hemorrhagic stroke undergoing intracranial pressure (ICP) and brain temperature monitoring.

Mechanism based neurotoxicity of mGlu5 positive allosteric modulators--development challenges for a promising novel antipsychotic target.

Previous work has suggested that activation of mGlu5 receptor augments NMDA receptor function and thereby may constitute a rational approach addressing glutamate hypofunction in schizophrenia and a target for novel antipsychotic drug development. Here, we report the in vitro activity, in vivo efficacy and safety profile of 5PAM523 (4-Fluorophenyl){(2R,5S)-5-[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]-2-methylpiperidin-1-yl}methanone), a structurally novel positive allosteric modulator selective of mGlu5. In cells expressing human mGlu5 receptor, 5PAM523 potentiated threshold responses to glutamate in fluorometric calcium assays, but does not have any intrinsic agonist activity.

ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization.

Metabotropic glutamate receptor 7 (mGlu(7)) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu(7) negative allosteric modulator (NAM) (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743). In vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(+)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor.

Stroke-related Early Tracheostomy versus Prolonged Orotracheal Intubation in Neurocritical Care Trial (SETPOINT): a randomized pilot trial.

Background And Purpose: Optimal timing of tracheostomy in ventilated patients with severe stroke is unclear. We aimed to investigate feasibility, safety, and potential advantages of early tracheostomy in these intensive care unit (ICU) patients.

Methods: This prospective, randomized, parallel-group, controlled, open, and outcome-masked pilot trial was conducted in neurological/neurosurgical ICUs of a university hospital.

Volatile isoflurane sedation in cerebrovascular intensive care patients using AnaConDa(®): effects on cerebral oxygenation, circulation, and pressure.

Purpose: The anesthetic-conserving device AnaConDa(®), a miniature vaporizer, allows volatile sedation in the intensive care unit (ICU). We investigated the effects of isoflurane sedation on cerebral and systemic physiology parameters in neuromonitored ICU stroke patients.

Methods: Included in the study were 19 consecutive ventilated patients with intracerebral hemorrhage (12), subarachnoid hemorrhage (4), and ischemic stroke (3) who were switched from intravenous propofol or midazolam to inhalative isoflurane sedation for an average of 3.

Amorphous solid dispersion successfully improved oral exposure of ADX71943 in support of toxicology studies.

ADX71943 is a potent and selective GABA(b) receptor positive allosteric modulator (PAM) which exhibits poor aqueous solubility at all physiologically relevant pHs. The aim of this study was to identify an adequate formulation to improve the solubility of ADX71943 to achieve a sufficiently high plasma exposure after oral administration to support the toxicology program. Considering the overall physicochemical properties and the low solubility of ADX71943 in a variety of solvents, solid dispersion, and particle size reduction have been successfully chosen as potential strategies to improve its oral bioavailability.

[Electrocardiographic identification of the culprit artery and occlusion site in ST-elevation myocardial infarction].

Background: In clinical practice, the identification of the culprit vessel and the localization of the occlusion site in ST-elevation myocardial infarction (STEMI) are provided by coronary angiography. Over the last few years, however, an increasing body of literature focused upon the reassessment of the ECG as a reliable technique to obtain this useful information. The aim of this study was to evaluate the accuracy of electrocardiographic criteria compared to coronary angiography.

A potent and selective metabotropic glutamate receptor 4 positive allosteric modulator improves movement in rodent models of Parkinson's disease.

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) have been proposed as a novel therapeutic approach for the treatment of Parkinson's disease. However, evaluation of this proposal has been limited by the availability of appropriate pharmacological tools to interrogate the target. In this study, we describe the properties of a novel mGluR4 PAM.

A multi-element psychosocial intervention for early psychosis (GET UP PIANO TRIAL) conducted in a catchment area of 10 million inhabitants: study protocol for a pragmatic cluster randomized controlled trial.

Background: Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services.

Methods/design: The Psychosis early Intervention and Assessment of Needs and Outcome (PIANO) trial is part of a larger research program (Genetics, Endophenotypes and Treatment: Understanding early Psychosis - GET UP) which aims to compare, at 9 months, the effectiveness of a multi-component psychosocial intervention versus treatment as usual (TAU) in a large epidemiologically based cohort of patients with FEP and their family members recruited from all public community mental health centers (CMHCs) located in two entire regions of Italy (Veneto and Emilia Romagna), and in the cities of Florence, Milan and Bolzano. The GET UP PIANO trial has a pragmatic cluster randomized controlled design.

Discovery of 1,4-disubstituted 3-cyano-2-pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.

The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties.

Emotional anticipation rather than processing is altered in patients with vasovagal syncope.

Objective: To investigate whether the electrocortical activity underlying the anticipation and processing of emotional stimuli is enhanced in individuals with recurrent episodes of vasovagal syncope (VVS).

Methods: Fifteen fainters and 15 age-matched healthy controls were presented a S1-S2 task, where the content of high-arousal pleasant and unpleasant, and neutral pictures (S2) was forecasted by word cues (S1). Stimulus Preceding Negativity (SPN) amplitude during the S1-S2 interval was computed as a measure of affective anticipation.

MRI in patients with acute basilar artery occlusion - DWI lesion scoring is an independent predictor of outcome.

Aims: We analyzed early diffusion-weighted magnetic resonance imaging of patients with acute basilar artery occlusion by applying different lesion scoring systems and determined their predictive value for favorable outcome.

Methods: Between 1998 and 2010, patients with confirmed basilar artery occlusion were entered in a local database. magnetic resonance imaging angiography was performed for diagnosis of basilar artery occlusion and/or during initiated recanalization therapy.

Autonomic effects of intraventricular extension in intracerebral hemorrhage.

Background: Autonomic dysfunction after stroke is common and relates to unfavorable outcome. The pathophysiology of autonomic impairment after intracerebral hemorrhage (ICH) is unknown. This study examined the relationship between intraventricular hemorrhage extension (IVH) and autonomic dysregulation after ICH.

Design and commissioning of a high magnetic field muon spin relaxation spectrometer at the ISIS pulsed neutron and muon source.

The high magnetic field (HiFi) muon instrument at the ISIS pulsed neutron and muon source is a state-of-the-art spectrometer designed to provide applied magnetic fields up to 5 T for muon studies of condensed matter and molecular systems. The spectrometer is optimised for time-differential muon spin relaxation studies at a pulsed muon source. We describe the challenges involved in its design and construction, detailing, in particular, the magnet and detector performance.

Decompressive surgery in cerebrovenous thrombosis: a multicenter registry and a systematic review of individual patient data.

Background And Purpose: Herniation attributable to unilateral mass effect is the major cause of death in cerebral venous thrombosis (CVT). Decompressive surgery may be lifesaving in these patients.

Methods: Retrospective registry of cases of acute CVT treated with decompressive surgery (craniectomy or hematoma evacuation) in 22 centers and systematic review of all published cases of CVT treated with decompressive surgery.

Association of non-diabetic hyperglycemia with autonomic shift in acute ischaemic stroke.

Background And Purpose: The etiology of hyperglycemia in acute stroke remains controversial. It is unclear whether hyperglycemia arises as an epiphenomenon of stroke or as a reflection of underlying diabetes. Autonomic shift to sympathetic overactivity has been repeatedly observed in acute stroke.

International normalised ratio normalisation in patients with coumarin-related intracranial haemorrhages--the INCH trial: a randomised controlled multicentre trial to compare safety and preliminary efficacy of fresh frozen plasma and prothrombin complex--study design and protocol.

Background: Intracerebral haemorrhage is the most feared complication in patients who are on treatment with vitamin K antagonists. Vitamin K antagonist related intracerebral haemorrhage occurs in about 10% of patients. Intracerebral haemorrhage has the worst prognosis of all subtypes of stroke including spontaneous intracerebral haemorrhage, and a mortality rate of up to about 65%.

Autonomic shift and increased susceptibility to infections after acute intracerebral hemorrhage.

Background And Purpose: High infection rate after severe stroke may partly relate to brain-induced immunodepression syndrome. However, the underlying pathophysiology remains unclear. The aim of the current study was to investigate the role of autonomic shift in increased susceptibility to infection after acute intracerebral hemorrhage (ICH).