A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator.

Aims: A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI-291 is an allosteric modulator of GCase, enhancing its activity.

Lack of Detection of the Analgesic Properties of PF-05089771, a Selective Na 1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects.

Sodium channel blockers are used for the treatment of pain, but this is limited by the lack of selectivity for different sodium channel subtypes, which can result in central nervous system and cardiovascular side effects. As such, there is special interest in the Na 1.7 subtype, which is expressed predominantly in nociceptive and sympathetic neurons.

Analgesic potential of PF-06372865, an α2/α3/α5 subtype-selective GABA partial agonist, in humans.

Background: This study investigated the analgesic effects of two doses (15 and 65 mg) of PF-06372865, a novel α2/α3/α5 gamma-aminobutyric acid A (GABA) subunit selective partial positive allosteric modulator (PAM), compared with placebo and pregabalin (300 mg) as a positive control.

Methods: We performed a randomised placebo-controlled crossover study (NCT02238717) in 20 healthy subjects, using a battery of pain tasks (electrical, pressure, heat, cold and inflammatory pain, including a paradigm of conditioned pain modulation). Pharmacodynamic measurements were performed at baseline and up to 10 h after dose.

Reproducibility of a battery of human evoked pain models to detect pharmacological effects of analgesic drugs.

Background: Although reproducibility is considered essential for any method used in scientific research, it is investigated only rarely; thus, strikingly little has been published regarding the reproducibility of evoked pain models involving human subjects. Here, we studied the reproducibility of a battery of evoked pain models for demonstrating the analgesic effects of two analgesic compounds.

Methods: A total of 81 healthy subjects participated in four studies involving a battery of evoked pain tests in which mechanical, thermal and electrical stimuli were used to measure pain detection and tolerance thresholds.

The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia.

Background: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder .

The ultraviolet B inflammation model: Postinflammatory hyperpigmentation and validation of a reduced UVB exposure paradigm for inducing hyperalgesia in healthy subjects.

Background: Pain models are commonly used in drug development to demonstrate analgesic activity in healthy subjects and should therefore not cause long-term adverse effects. The ultraviolet B (UVB) model is a model for inflammatory pain in which three times the minimal erythema dose (3MED) is typically applied to induce sensitization. Based on reports of long-lasting postinflammatory hyperpigmentation (PIH) associated with 3MED, it was decided to investigate the prevalence of PIH among subjects who were previously exposed to 3MED at our research centre.

Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABA receptor positive allosteric modulator PF-06372865.

Background And Purpose: Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABA receptors, have significant side effects that limit their clinical utility. As many of these side effects are mediated by the α1 subunit, there has been a concerted effort to develop α2/3 subtype-selective PAMs.

Experimental Approach: In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits.

Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models.

Aim: Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first-in-class molecule in humans.

The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study.

Rationale: The purpose of this study is to evaluate the single dose effect of intranasal esketamine (84 mg) compared to placebo on on-road driving performance. Mirtazapine (oral, 30 mg) was used as a positive control, as this antidepressant drug is known to negatively affect driving performance.

Methods: Twenty-six healthy volunteers aged 21 to 60 years were enrolled in this study.

Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-tetrahydrocannabinol in Patients WithProgressive Multiple Sclerosis.

Purpose: The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS).

Methods: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled.

The use of a battery of pain models to detect analgesic properties of compounds: a two-part four-way crossover study.

Aim: The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects.

Methods: The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)-pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg , phenytoin 300 mg, (S)-ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II).

A literature review on the pharmacological sensitivity of human evoked hyperalgesia pain models.

Aims: Human evoked pain models can be used to determine the efficacy of new and existing analgesics and to aid in the identification of new targets. Aspects of neuropathic pain can be simulated by inducing hyperalgesia resulting from provoked sensitization. The present literature review aimed to provide insight into the sensitivity of different hyperalgesia and allodynia models of pharmacological treatment.

Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery.

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug's pharmacology and identify potentially suitable therapeutic populations. The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can mimic the complex nature of clinical pain.

Responsiveness of electrical nociceptive detection thresholds to capsaicin (8 %)-induced changes in nociceptive processing.

Pain disorders can be initiated and maintained by malfunctioning of one or several mechanisms underlying the nociceptive function. Psychophysical procedures allow the estimation of nociceptive detection thresholds using intra-epidermal electrical stimuli. By varying the temporal properties of electrical stimuli, various contributions of nociceptive processes to stimulus processing can be observed.