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Impact of a selective cyclooxygenase-2 inhibitor, celecoxib, on cortical excitability and electrophysiological properties of the brain in healthy volunteers: A randomized, double-blind, placebo-controlled study.

ABSTRACT: The inflammatory response is considered a defence mechanism against physical or infectious insults and is prevalent within the central nervous system. Seizures also result in a robust inflammatory cascade, leading to enhanced activation of excitatory synaptic networks. Ample evidence based on animal models of epilepsy has demonstrated that celecoxib, a highly selective inhibitor of cyclooxygenase-2, has anticonvulsant effects. We aimed to evaluate the impact of celecoxib on the cortical excitability and electrophysiological properties of the brain in healthy humans. Electroencephalography (EEG) or transmagnetic stimulation (TMS) was used to measure neurophysiological activity. Forty healthy volunteers were randomized to 4 groups (n = 10 in each group): 1) celecoxib and EEG, 2) placebo and EEG, 3) celecoxib and TMS, and 4) placebo and TMS. For the EEG study, resting EEG was performed at baseline just before administering 400 mg of celecoxib or placebo and repeated 4 hours after administration. The subjects took 200 mg of celecoxib or placebo twice a day for 7 subsequent days, and a third EEG was conducted 4 hours after the final dose. Power spectra were compared at each time point. For the TMS study, the resting motor threshold (RMT), motor evoked potential (MEP) peak-to-peak amplitude, and cortical silent period (CSP) were measured at baseline and after taking 200 mg of celecoxib or placebo twice a day for 7 days. Celecoxib did not significantly change brain activity in the EEG study. However, the sum of power recorded from all electrodes tended to increase in the celecoxib group only at 4 hours after administration (p = 0.06). In detail, one dose of celecoxib (400 mg) transiently and significantly increased the alpha band power recorded in the frontal and parietal areas as well as in the whole brain (p = 0.049, 0.017, and 0.014, respectively) and the beta frequency in the central and parietal regions (p = 0.013 and 0.005, respectively), whereas the placebo did not. This effect was abolished after 7 days of treatment. In the TMS study, we found no statistically significant change in the RMT, MEP peak-to-peak amplitude or CSP. This evidence suggests that celecoxib transiently alters the electrophysiological properties of the brain but does not suppress neuronal excitability in healthy humans.

SUBMITTER: Lim JA

PROVIDER: S-EPMC6386435 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Impact of a selective cyclooxygenase-2 inhibitor, celecoxib, on cortical excitability and electrophysiological properties of the brain in healthy volunteers: A randomized, double-blind, placebo-controlled study.

Lim Jung-Ah JA Jung Ki-Young KY Park Boram B Kim Tae-Joon TJ Jun Jin-Sun JS Kim Keun Tae KT Yang Tae-Won TW Lee Soon-Tae ST Jung Keun-Hwa KH Chu Kon K Lee Sang Kun SK Park Kyung-Il KI

PloS one 20190222 2

The inflammatory response is considered a defence mechanism against physical or infectious insults and is prevalent within the central nervous system. Seizures also result in a robust inflammatory cascade, leading to enhanced activation of excitatory synaptic networks. Ample evidence based on animal models of epilepsy has demonstrated that celecoxib, a highly selective inhibitor of cyclooxygenase-2, has anticonvulsant effects. We aimed to evaluate the impact of celecoxib on the cortical excitabi ...[more]

PMID: 30794658

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Project description:BackgroundDasiglucagon is a novel glucagon analog that is stable in aqueous formulation and approved for use in severe hypoglycemia. Concentration QTc analyses are critical for assessing risk of drug-induced QTc prolongation and potential for fatal cardiac arrhythmias such as torsades de pointes.ObjectiveThe aim of this study was to determine whether dasiglucagon treatment resulted in any clinically relevant effect on cardiac repolarization in healthy volunteers.MethodsThis double-blind, placebo-controlled, dose-escalation Phase I trial was conducted at a single center in Germany between November 2018 and June 2019. Sixty healthy volunteers aged 18 to 45 years were randomized within dose cohorts to receive intravenous dasiglucagon, intravenous placebo, or subcutaneous dasiglucagon. In the intravenous administration cohorts, doses ranged from 0.03 mg to 1.5 mg. The subcutaneous administration cohort received the approved 0.6 mg dose. In the intravenous administration cohorts, serial electrocardiograms were extracted from continuous Holter monitors at prespecified time points beginning the day before dosing and through 24 hours postdose. Heart rate, PR interval, and QRS duration were evaluated. Concentration-QT analyses corrected by Fridericia's formula (QTcF) were performed using both a linear mixed-effects and a maximum estimated effect (Emax) model.ResultsAt the doses studied, dasiglucagon did not have any clinically relevant effect on heart rate, PR interval, or QRS duration. A minor prolongation of the QTcF interval was observed without any clear dose or concentration dependency. Both the linear and Emax models predicted mean and 90% CIs of placebo-corrected change in QTcF remained below 10 ms (the threshold of regulatory concern), although the linear model did not fit the data well at low dasiglucagon plasma concentrations. In the Emax model, the Emax of dasiglucagon was 3.6 ms (90% CI, 1.23-5.95 ms), and the amount to produce half the effect of Emax) was 426.0 pmol/L (90% CI, -48.8 to 900.71 pmol/L). The treatment effect-specific intercept was -0.44 ms (90% CI, -2.37 to 1.49 ms). The most frequently observed treatment-emergent adverse events reported in the trial were gastrointestinal disorders such as nausea and vomiting.ConclusionsDasiglucagon does not cause clinically relevant QTc prolongation in concentrations up to ≈30,000 pmol/L, a level 5-fold higher than the highest observed plasma concentrations in clinical trials investigating use of the approved 0.6 mg SC dose. ClinicalTrials.gov Identifier: NCT03735225; EudraCT identifier: 2018-002025-32. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

Project description:Background and rationaleAtypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.Methodology/principal findingsA double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18-30 years old, BMI 18.5-25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.Conclusions/significanceOlanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.Trial registrationClinicalTrials.gov NCT00741026.

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Dataset Information

Impact of a selective cyclooxygenase-2 inhibitor, celecoxib, on cortical excitability and electrophysiological properties of the brain in healthy volunteers: A randomized, double-blind, placebo-controlled study.

Publications

Impact of a selective cyclooxygenase-2 inhibitor, celecoxib, on cortical excitability and electrophysiological properties of the brain in healthy volunteers: A randomized, double-blind, placebo-controlled study.

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