Evaluation of the pharmacokinetic interactions and safety of atogepant coadministered with esomeprazole.

Aim: To investigate potential pharmacokinetic interactions between atogepant and esomeprazole. Methods: Atogepant, esomeprazole, or both were administered to 32 healthy adults in an open-label, nonrandomized, crossover study. Systemic exposure (area under the plasma concentration-time curve [AUC] and peak plasma concentration [Cmax]) for atogepant administered in combination versus alone were compared using a linear mixed effects model. Results: Coadministration with esomeprazole delayed atogepant time to Cmax by ∼1.5 h and reduced Cmax by ∼23% with no statistically significant change in AUC compared with atogepant alone. Administration of atogepant 60 mg alone or in combination with esomeprazole 40 mg was well tolerated in healthy adults. Conclusion: Esomeprazole had no clinically meaningful effect on atogepant pharmacokinetics. Clinical Trial Registration: unregistered phase I study.

A clinical study was conducted in 32 healthy adults to evaluate the possibility of interactions between atogepant, a new drug for the prevention of migraine, and esomeprazole, a drug used to reduce stomach acid. The participants of the study were given each drug alone and together to understand the effect they had on the body's ability to absorb, distribute, and excrete each drug alone and together. The results of this study show that there are no clinically important changes in how atogepant is processed by the body when administered with esomeprazole, and they can be safely taken together.

A randomized, multicenter trial assessing the effects of rapastinel compared to ketamine, alprazolam, and placebo on simulated driving performance.

N-methyl-D-aspartate ionotropic glutamatergic receptor (NMDAR) modulators, including rapastinel and ketamine, elicit rapid and sustained antidepressant responses in patients with treatment-resistant major depressive disorder. This phase I, randomized, multicenter, placebo-controlled, five-period, crossover, single-dose study evaluated simulated driving performance of healthy participants (N = 107) after single doses of rapastinel slow intravenous (i.v.) bolus 900 and 1800 mg, alprazolam oral 0.75 mg (positive control), ketamine i.v. infusion 0.5 mg/kg (clinical comparator), and placebo ~ 45 min before driving. The primary end point was SD of lateral position (SDLP) during the 60-min 100-km simulated driving scenario. Additional measures of driving performance, sleepiness, and cognition were also evaluated. To assess effects over time, mean SDLP was calculated for each 10-min interval of driving. Sensitivity of the assays was confirmed with alprazolam (all placebo comparisons p < 0.02). Rapastinel 900 and 1800 mg did not significantly affect simulated driving performance compared to placebo (both p > 0.5). Both rapastinel doses resulted in significantly less impaired driving compared to alprazolam or ketamine (all p < 0.002); ketamine significantly impaired driving compared to placebo (p = 0.0001). Results for the additional measures were similar to the primary end point. No new safety signals were observed for any study interventions. This first study of rapastinel effects on simulated driving found that rapastinel 900 and 1800 mg did not impair driving performance, but ketamine 0.5 mg/kg resulted in significantly impaired driving performance. Ketamine's effects on driving were maintained for at least 105 min, indicating that clinicians should be vigilant to prevent or postpone driving in patients after ketamine treatment.

Blockade of nicotinic receptors of bovine adrenal chromaffin cells by nanomolar concentrations of atropine.

Nanomolar concentrations of atropine have been considered up to now to be selective for blockade of muscarinic receptors for acetylcholine. A collateral finding indicated to us that these low concentrations of atropine could also target the neuronal nicotinic receptors. We report here a detailed study on this novel property of atropine. Catecholamine release, measured on-line with amperometry in chromaffin cells stimulated with acetylcholine pulses was blocked by atropine in a competitive manner. To corroborate a direct action of atropine on nicotinic receptors, we have employed N,N-dimethyl-N'-phenyl-piperazinium (DMPP), a pure nicotinic receptor agonist; atropine blocked its secretory responses with an IC50 of 2.04 nM. Nicotinic currents, recorded with the whole cell configuration of the patch-clamp technique were blocked by atropine in a concentration-dependent manner (IC50 of 11 nM), also showing a competitive nature. Nicotinic receptor currents in oocytes expressing bovine alpha7 and alpha3beta4 nicotinic receptors were blocked by atropine with an IC50 of 11.2 and 46.8 nM, respectively. Atropine (30 nM) also decreased the increment of the cytosolic calcium concentrations after stimulation with 30 microM DMPP in bovine chromaffin cells. However, action potentials evoked by DMPP were not modified by atropine. Our results demonstrate that nicotinic currents and their downstream consequences (i.e. cytosolic calcium elevations and catecholamine release) were blocked by nanomolar concentrations of atropine; although the blockade was partial, it must be considered when using atropine to study cholinergic neurotransmission, particularly at synapses where both nicotinic and muscarinic receptors are present i.e., the adrenal medulla and autonomic ganglia.

Activation and blockade by choline of bovine alpha7 and alpha3beta4 nicotinic receptors expressed in oocytes.

Choline, the precursor and the metabolite of acetylcholine, is reputed as a selective alpha7 nicotinic receptor agonist. In this study, however, we have seen that choline exerted a dual effect on bovine nicotinic receptors expressed in Xenopus oocytes. On the one hand, choline behaved as a weak full agonist on bovine alpha7-mediated inward currents, with an EC50 of 0.43 mM. On the other, choline blocked bovine alpha3beta4 currents, with an IC50 of 0.97 mM. The blockade by choline was fast (tau(on), 0.36 s), fully reversible (tau(off), 1.23 s), exhibited voltage-dependence (60% blockade at -100 mV and 30% blockade at -40 mV), and was of a non-competitive nature, suggesting an open-channel type of alpha3beta4 receptor blockade. Thus, choline by activating alpha7 receptors and/or blocking alpha3beta4 receptors might play a physiological role in the control of neurotransmission at cholinergic synapses where alpha7 and alpha3beta4 receptor are expressed.

A choline-evoked [Ca2+]c signal causes catecholamine release and hyperpolarization of chromaffin cells.

In bovine chromaffin cells fast-superfused with Krebs-HEPES solution containing 1-2 mM Ca2+, 5 s pulses of choline (1-10 mM), elicited catecholamine secretory responses that were only approximately 10% of those evoked by ACh (0.01-0.1 mM). However, in high-Ca2+ solutions (10-20 mM) the size of the choline secretory responses approached those of ACh. The choline responses (10 mM choline in 20 mM Ca2+, 10Cho/20Ca2+) tended to decline upon repetitive pulsing, whereas those of ACh were well maintained. The confocal [Ca2+]c increases evoked by 10Cho/20Ca2+ were similar to those of ACh. Whereas 10Cho/20Ca2+ caused mostly hyperpolarization of chromaffin cells, 0.1ACh/20 Ca2+ caused first depolarization and then hyperpolarization; in regular solutions (2 mM Ca2+), the hyperpolarizing responses did not show up. In Xenopus oocytes injected with mRNA for bovine alpha7 nicotinic receptors (nAChRs), 10Cho/20 Ca2+ fully activated an inward current; in oocytes expressing alpha3beta4, however, the inward current elicited by choline amounted to only 4% of the size of alpha7 current. Our results suggest that choline activates the entry of Ca2+ through alpha7 nAChRs; this leads to a cytosolic concentration of calcium ([Ca2+]c) rise that causes the activation of nearby Ca2+-dependent K+ channels and the hyperpolarization of the chromaffin cell. This response, which could be unmasked provided that cells were stimulated with high-Ca2+ solutions, may be the underlying mechanism through which choline exerts a modulatory effect on the electrical activity of the chromaffin cell and on neurotransmitter release at cholinergic synapses.