Treosulfan vs busulfan conditioning for allogeneic bmt in children with nonmalignant disease: a randomized phase 2 trial.

Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This prospective, randomized, phase 2 trial compared safety and efficacy of busulfan with treosulfan based preparative regimens. Children with non-malignant diseases received fludarabine and either intravenous (IV) busulfan (4.

Population pharmacokinetic modeling of treosulfan and rationale for dose recommendation in children treated for conditioning prior to allogeneic hematopoietic stem cell transplantation.

Intravenously infused treosulfan was evaluated in adult and pediatric patients for conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. A population pharmacokinetic (PK) model was initially developed on 116 adult and pediatric PK profiles from historical trials, to support treosulfan dose recommendations for children in 2 prospective trials. The aim was to assess and update the initial population PK model by inclusion of additional 83 pediatric PK profiles from these 2 trials.

Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs).

The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP).

For over 40 years, the National Institute of Neurological Disorders and Stroke/National Institutes of Health-funded Anticonvulsant Screening Program has provided a preclinical screening service for participants world-wide that helped identify/characterize new antiseizure compounds, a number of which advanced to the market for the treatment of epilepsy. The newly-renamed Epilepsy Therapy Screening Program (ETSP) has a refocused mission to identify novel agents which will help address the considerable remaining unmet medical needs in epilepsy. These include identifying antiseizure agents for treatment-resistant epilepsy, as well as anti-epileptogenic agents that will prevent the development of epilepsy or disease-modifying agents that will ameliorate or even cure established epilepsy and its comorbidities.

The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats.

Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats.

Electrophysiological evidence for rapid 5-HT₁A autoreceptor inhibition by vilazodone, a 5-HT₁A receptor partial agonist and 5-HT reuptake inhibitor.

This study examined the effect of vilazodone, a combined serotonin (5-HT) reuptake inhibitor and 5-HT(1A) receptor partial agonist, paroxetine and fluoxetine on the sensitivity of 5-HT(1A) autoreceptors of serotonergic dorsal raphe nucleus neurons in rats. These effects were assessed by determining the intravenous dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) required to suppress the basal firing rate of these neurons by 50% (ID₅₀) in anesthetized rats using in vivo electrophysiology. 5-HT uptake inhibition was determined by the ability of the compounds to reverse (±)-p-chloroamphetamine (PCA)-induced rat hypothalamic 5-HT depletion ex vivo.

The pharmacokinetics and pharmacodynamics of zaleplon delivered as a thermally generated aerosol in a single breath to volunteers.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of inhaled zaleplon were assessed in healthy volunteers. Forty participants received 0.5, 1, 2, or 4 mg zaleplon or placebo as a thermally generated aerosol in a randomized, double-blind, parallel-group, dose escalation study.

Targeting memory processes with drugs to prevent or cure PTSD.

Introduction: Post-traumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder resulting from exposure to a severe traumatic stressor and an area of great unmet medical need. Advances in pharmacological treatments beyond the currently approved SSRIs are needed.

Areas Covered: Background on PTSD, as well as the neurobiology of stress responding and fear conditioning, is provided.

Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine.

Objective: The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder.

Methods: A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system.

Discovery of N-(1-ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98-2): an orally active corticotropin releasing factor-1 (CRF-1) receptor antagonist.

The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography.

Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine.

Background: There is a need for a rapid-acting, non-injection, acute treatment for agitation.

Aims: To evaluate inhaled loxapine for acute treatment of agitation in schizophrenia.

Method: This phase III, randomised, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.

Emergence of anti-conflict effects of zolpidem in rhesus monkeys following extended post-injection intervals.

Rationale: Zolpidem is a hypnotic drug that binds to γ-aminobutyric acid type A receptors but lacks consistently demonstrable anxiolytic efficacy.

Methods: Rhesus monkeys (N = 4) were trained under a multiple schedule in which food-maintained responding was programmed (18-response fixed ratio) for a 5-min period, followed by a 5-min period in which the food-maintained responding was suppressed by response-contingent electric shock (20-response fixed ratio). Doses of zolpidem (range = 0.

Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models.

Adaptive responding to threatening stressors is of fundamental importance for survival. Dysfunctional hyperactivation of corticotropin releasing factor type-1 (CRF(1)) receptors in stress response system pathways is linked to stress-related psychopathology and CRF(1) receptor antagonists (CRAs) have been proposed as novel therapeutic agents. CRA effects in diverse animal models of stress that detect anxiolytics and/or antidepressants are reviewed, with the goal of evaluating their potential therapeutic utility in depression, anxiety, and other stress-related disorders.

The dopamine D(2) receptor partial agonist aplindore improves motor deficits in MPTP-treated common marmosets alone and combined with L-dopa.

Dopamine replacement therapy in Parkinson's disease (PD) using L-dopa is invariably associated with a loss of drug efficacy ("wearing off") and the onset of dyskinesia. The use of dopamine receptor partial agonists might improve therapeutic benefit without increased dyskinesia expression but may antagonise the effects of L-dopa. We now examine the effects of the novel high affinity, dopamine D(2) receptor partial agonist, aplindore alone and in combination with L-dopa in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset.

Retrograde effects of triazolam and zolpidem on sleep-dependent motor learning in humans.

Drugs that act as allosteric activators at the benzodiazepine site of the gamma-aminobutyric acid (GABA(A)) receptor complex are used commonly to treat insomnia but relatively little is known of how such use affects learning and memory. Although anterograde effects on memory acquisition have been shown, possible retrograde effects on consolidation are more relevant when such agents are administered at bedtime. We tested the effects of two GABA(A) allosteric activators on sleep-dependent motor skill memory consolidation in 12 healthy male subjects.

D2 receptor partial agonists: treatment of CNS disorders of dopamine function.

A remarkable diversity of psychiatric and neurological disorders have been associated with dysfunction of dopamine (DA)-containing neurons, including schizophrenia, bipolar disorder (BD), Parkinson's disease (PD), and restless legs syndrome (RLS). In such disorders, transmission in discrete DA pathways may range from hypoactivation to hyperactivation of DA receptors, particularly those of the D(2) subtype, providing the rationale for treatment approaches that activate or block D(2) receptors, respectively. However, full agonists or pure D(2) receptor antagonists may not be optimal therapeutic approaches for their respective disorders for a number of reasons, including an inability to restore the aberrant DA pathways to a normal level of basal tone.

2-Arylpyrimidines: novel CRF-1 receptor antagonists.

The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.

The design, synthesis and structure-activity relationships of 1-aryl-4-aminoalkylisoquinolines: a novel series of CRF-1 receptor antagonists.

The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.

The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders.

The present review focuses on the corticotropin releasing factor type 1 (CRF(1)) receptor as a novel target for treating depression, anxiety and other stress-related disorders. An organism's stress response system is a complex network of neuronal, endocrine and autonomic pathways which has evolved to provide adaptive reactions to severe environmental and physiological stressors. The peptide CRF plays a critical role in the proper functioning of the stress response system through its actions on CRF(1) receptors located at multiple anatomical sites.

Inflammation-induced reduction of spontaneous activity by adjuvant: A novel model to study the effect of analgesics in rats.

The majority of rodent models used to evaluate analgesic drug effects rely on evoked measures of nociceptive thresholds as primary outcomes. These approaches are often time-consuming, requiring extensive habituation sessions and repeated presentations of eliciting stimuli, and are prone to false-positive outcomes due to sedation or tester subjectivity. Here, we describe the reduction of spontaneous activity by adjuvant (RSAA) model as an objective and quantifiable behavioral model of inflammatory pain that can predict the analgesic activity of a variety of agents following single-dose administration.

Non-peptidic CRF1 receptor antagonists for the treatment of anxiety, depression and stress disorders.

Anxiety and depression are psychiatric disorders that constitute a major health concern worldwide, and new pharmacological approaches with the potential for improved efficacy and decreased side effect profiles relative to currently marketed drugs are desired. Since the identification of corticotropin releasing factor (CRF) by Vale and colleagues in 1981, an extensive research effort has solidified the importance of this 41 amino acid peptide in mediating the body's behavioral, endocrine, and autonomic responses to stress. The further identification of CRF receptor subtypes has provided compelling targets for novel pharmaceutical agents.

Effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization anxiolytic test in rat pups.

CRF(1) receptor antagonists have been proposed as novel pharmacological treatments for depression, anxiety and stress disorders. The primary goal of the present study was to evaluate the effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization (SIV) model of anxiety. Nine- to 11-day-old rat pups were separated from their litter and the effects of intraperitoneally administered test compounds on the elicited ultrasonic vocalizations were measured.