The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study.

Objective: This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults.

Methods: Part 1 was a four-period dose-selection study (n = 8 complete). Part 2 was a two-period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory-related neuronal activity.

Target engagement and cellular fate of otelixizumab: a repeat dose escalation study of an anti-CD3ε mAb in new-onset type 1 diabetes mellitus patients.

Aims: This paper describes the pharmacological findings from a study where otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation.

Adjustment of the area under the concentration curve by terminal rate constant for bioequivalence assessment in a parallel-group study of lamotrigine.

Aim: A new strength of lamotrigine extended-release formulation unexpectedly failed to show bioequivalence with the existing strengths at the same dose in a parallel-group study. We report the post-hoc analyses conducted to identify the cause and propose an approach for future evaluations in similar situations.

Methods: A seemingly bimodal distribution of the half-life among the study participants prompted the use of terminal-phase-rate-constant-adjusted area under the concentration curve as the endpoint for bioequivalence assessment.

Systemic Pharmacokinetics, Safety, and Preliminary Efficacy of Topical AhR Agonist Tapinarof: Results of a Phase 1 Study.

Tapinarof cream is a novel topical nonsteroidal agent that represents a unique class of anti-inflammatory molecules targeting the aryl hydrocarbon receptor. Study 201851 was an open-label, 2-cohort sequential study that assessed the systemic pharmacokinetics, safety, and efficacy of tapinarof in adults with moderate to severe atopic dermatitis. A total of 11 participants were enrolled: 5 received 2% cream, and 6 received 1% cream.

Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial.

Background: Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1 mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS.

The relative bioavailability of 2 prototype fixed-dose combination formulations for amlodipine and rosuvastatin in healthy white and Chinese subjects.

A fixed-dose combination (FDC) may improve patient compliance and clinical outcomes in the management of cardiovascular risk in hypertensive and dyslipidemic patients. The study (NCT02075619) evaluated the bioavailability of 2 prototype FDC tablet formulations (FDC1 and FDC2) of amlodipine/rosuvastatin (10 mg/20 mg) compared with coadministered reference tablets. It was a randomized, single-dose, 3-way crossover pilot study in healthy white (n = 12) and Chinese (n = 12) adults.

A randomized, placebo-controlled trial of the analgesic efficacy and safety of the p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain from lumbosacral radiculopathy.

Objectives: Preclinical studies have demonstrated involvement of p38 mitogen-activated protein kinase signaling pathways in the development of persistent pain after peripheral nerve injury. A double-blind, randomized, placebo-controlled study was undertaken to evaluate the analgesic efficacy of losmapimod (GW856553), a novel p38α/β inhibitor, in patients with chronic neuropathic pain due to lumbosacral radiculopathy.

Materials And Methods: A total of 144 patients with at least moderate baseline pain intensity (average daily score of ≥4 on an 11-point pain intensity numeric rating scale) were randomized to receive losmapimod, 7.

Ozanezumab dose selection for amyotrophic lateral sclerosis by pharmacokinetic-pharmacodynamic modelling of immunohistochemistry data from patient muscle biopsies.

Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease with a high unmet medical need. In this context, a potential therapy should be brought to patients in the most expeditious way and early exploration of pharmacology is highly beneficial. Ozanezumab, a humanised IgG monoclonal antibody against Nogo-A protein which is an inhibitor of neurite outgrowth, is currently under development for the treatment of ALS and has been recently assessed in 76 patients in a first-in-human study.

Effect of hemodialysis on pharmacokinetics of ezogabine/retigabine and its N-acetyl metabolite in patients with end stage renal disease.

Ezogabine (EZG)/retigabine (RTG) and its metabolites are mainly eliminated renally. This Phase I study assessed the effect of hemodialysis on the pharmacokinetics of EZG/RTG and its N-acetyl metabolite (NAMR) in patients with end-stage renal disease; tolerability of EZG/RTG was a secondary endpoint. Patients (N=8) received EZG/RTG 100 mg orally 4 hours before (Period 1) or following (Period 2) dialysis.

Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial.

Unlabelled: The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET.

GSK1144814 is a potent, insurmountable antagonist at human NK₁ and NK₃ receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study.

Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study.

Background: Inhibitors of p38 mitogen-activated protein kinase are undergoing evaluation as a novel class of anti-rheumatic drugs, by virtue of their ability to suppress the production of pro-inflammatory cytokines. Emerging data suggests that they may also attenuate peripheral or central sensitization in neuropathic pain. A double-blind, placebo-controlled study was undertaken to evaluate the analgesic efficacy of losmapimod (GW856553), a novel p38α/β inhibitor, in subjects with neuropathic pain following traumatic peripheral nerve injury.

Pharmacokinetics and central nervous system effects of the novel dual NK1 /NK3 receptor antagonist GSK1144814 in alcohol-intoxicated volunteers.

Aims: Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1 /NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated.

Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers.

Purpose: Statins and antiepileptic drugs (AEDs) are frequently coprescribed to individuals with hypercholesterolemia and new-onset seizures. Statins are metabolized by the cytochrome P450 (CYP) enzyme system. Interactions between statins and agents that undergo CYP metabolism are common.

A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction.

Objectives: To evaluate the postoperative analgesic efficacy of GW842166, a noncannabinoid CB2 agonist, in patients undergoing third molar tooth extraction.

Methods: This randomized, double-blind, placebo-controlled study compared the analgesic efficacy of single doses of GW842166 (100 or 800 mg) or ibuprofen with placebo in patients undergoing extraction of at least 1 fully or partially impacted third molar tooth. Eligible participants were dosed preoperatively within 1 hour of surgery.

The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans.

TRPV1 is a cation channel activated by a range of noxious stimuli and highly expressed in nociceptive fibres. TRPV1 receptors are involved in pain and sensitisation associated with tissue injury and inflammation; hence, TRPV1 antagonists are potentially useful for the treatment of such pain states. SB-705498 is a potent, selective and orally bioavailable TRPV1 antagonist with demonstrated efficacy in a number of preclinical pain models.

Pharmacokinetics and tolerability of lamotrigine and olanzapine coadministered to healthy subjects.

Aim: To assess the pharmacokinetic effect and tolerability of lamotrigine 200 mg day(-1) and olanzapine 15 mg day(-1) coadministration in healthy male volunteers.

Methods: Subjects were randomized to receive either lamotrigine titrated on days 1-42 with olanzapine added on days 43-56 (LTG + OLZ group; N = 16), lamotrigine titration with placebo added on days 43-56 (LTG group; N = 12), or placebo on days 1-42 with olanzapine added on days 43-56 (OLZ group; N = 16). Steady state (0-24 h) pharmacokinetic profiles were determined on day 56 in each group.

Lack of pharmacokinetic interaction between oxcarbazepine and lamotrigine.

Epilepsy and bipolar disorder are commonly treated by combination drug therapy, such as lamotrigine and oxcarbazepine. To ensure the safety of this combination, information on pharmacokinetics and tolerability must be available. The objective of study was to evaluate the pharmacokinetics and tolerability of coadministered lamotrigine and oxcarbazepine in healthy subjects.

Pharmacokinetic profile of a new form of sumatriptan tablets in healthy volunteers.

Objective: Rapid delivery of migraine-specific medication to its site(s) of action is thought to be crucial in preventing or minimizing sensitization of central pain pathways and thereby in optimizing pain-free outcomes in patients with migraine. Sumatriptan has been developed as a new tablet formulation to enhance the rate of systemic drug delivery by improving tablet disintegration and drug dispersion relative to those of conventional tablets. These enhanced formulation characteristics may be beneficial during occurrences of the gastric stasis that can accompany migraine.

A hypersensitivity of glycogen phosphorylase activation in hearts of diabetic rats.

This study was initiated to determine whether glycogen phosphorylase activation was defective in hearts of alloxan diabetic rats. When hearts were perfused by gravity flow for 1 to 10 min with various concentrations of epinephrine, activation of glycogen phosphorylase in the diabetic was significantly greater at every time and epinephrine concentration than that seen in the normal. Cyclic AMP accumulation and protein kinase activation by epinephrine in the diabetic were not appreciably different or were lower than the normal responses to the hormone.