Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics.

Background: Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics.

Breathing variability during propofol/remifentanil procedural sedation with a single additional dose of midazolam or s-ketamine: a prospective observational study.

Purpose: Regulation of spontaneous breathing is highly complex and may be influenced by drugs administered during the perioperative period. Because of their different pharmacological properties we hypothesized that midazolam and s-ketamine exert different effects on the variability of minute ventilation (MV), tidal volume (TV) and respiratory rate (RR).

Methods: Patients undergoing procedural sedation (PSA) with propofol and remifentanil received a single dose of midazolam (1-3 mg, n = 10) or s-ketamine (10-25 mg, n = 10).

Breathing variability-implications for anaesthesiology and intensive care.

The respiratory system reacts instantaneously to intrinsic and extrinsic inputs. This adaptability results in significant fluctuations in breathing parameters, such as respiratory rate, tidal volume, and inspiratory flow profiles. Breathing variability is influenced by several conditions, including sleep, various pulmonary diseases, hypoxia, and anxiety disorders.

Variations in respiratory rate do not reflect changes in tidal volume or minute ventilation after major abdominal surgery.

Monitoring of postoperative pulmonary function usually includes respiratory rate and oxygen saturation measurements. We hypothesized that changes in postoperative respiratory rate do not correlate with changes in tidal volume or minute ventilation. In addition, we hypothesized that variability of minute ventilation and tidal volume is larger than variability of respiratory rate.

Mathematical modeling of the glucagon challenge test.

A model for the homeostasis of glucose through the regulating hormones glucagon and insulin is described. It contains a subsystem that models the internalization of the glucagon receptor. Internalization is a mechanism in cell signaling, through which G-protein coupled receptors are taken from the surface of the cell to the endosome.

No synergistic effect of subtherapeutic doses of donepezil and EVP-6124 in healthy elderly subjects in a scopolamine challenge model.

Introduction: Donepezil is a widely used cholinesterase inhibitor in the management of Alzheimer's disease. Despite large-scaled evidence for its efficacy, elevated peripheral ACh levels often lead to side effects and are dose limiting. The present exploratory study is designed to determine the potentiation of the effects of donepezil by cotreatment with EVP-6124, an alpha-7 nicotinic agonist, to reduce scopolamine-induced cognitive deficits in healthy elderly subjects.

A Computerized Test Battery to Study Pharmacodynamic Effects on the Central Nervous System of Cholinergic Drugs in Early Phase Drug Development.

Investigating potential pharmacodynamic effects in an early phase of central nervous system (CNS) drug research can provide valuable information for further development of new compounds. A computerized and thoroughly validated battery of neuropsychological and neurophysiological tests has been shown to be sensitive to detect drug-induced effects of multiple new and existing compounds. The test battery covers the main CNS domains, which have been shown to respond to drug effects and can be repeatedly administered following drug administration to characterize the concentration-effect profile of a drug.

Reversal of mecamylamine-induced effects in healthy subjects by nicotine receptor agonists: Cognitive and (electro) physiological responses.

Aims: Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor.

Methods: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine.

Results: Thirty-three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double-dummy).

EEG machine learning for accurate detection of cholinergic intervention and Alzheimer's disease.

Monitoring effects of disease or therapeutic intervention on brain function is increasingly important for clinical trials, albeit hampered by inter-individual variability and subtle effects. Here, we apply complementary biomarker algorithms to electroencephalography (EEG) recordings to capture the brain's multi-faceted signature of disease or pharmacological intervention and use machine learning to improve classification performance. Using data from healthy subjects receiving scopolamine we developed an index of the muscarinic acetylcholine receptor antagonist (mAChR) consisting of 14 EEG biomarkers.

An anti-nicotinic cognitive challenge model using mecamylamine in comparison with the anti-muscarinic cognitive challenge using scopolamine.

Aims: The muscarinic acetylcholine receptor antagonist scopolamine is often used for proof-of-pharmacology studies with pro-cognitive compounds. From a pharmacological point of view, it would seem more rational to use a nicotinic rather than a muscarinic anticholinergic challenge to prove pharmacology of a nicotinic acetylcholine receptor agonist. This study aims to characterize a nicotinic anticholinergic challenge model using mecamylamine and to compare it to the scopolamine model.

Pharmacokinetics and pharmacodynamics of oral mecamylamine - development of a nicotinic acetylcholine receptor antagonist cognitive challenge test using modelling and simulation.

A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects. A one-compartment linear kinetic model best described the plasma concentrations of mecamylamine.

No evidence of potentiation of buprenorphine by milnacipran in healthy subjects using a nociceptive test battery.

Background: Serotonin-norepinephrine reuptake inhibitors inhibit the reuptake of serotonin and noradrenalin and are used in the treatment of neuropathic pain. Animal studies suggest that milnacipran co-administered with opioids may potentiate the analgesic effect of μ-opioid receptor agonists. This study hypothesized that co-administration of milnacipran and buprenorphine would have a synergistic effect in evoked pain models in healthy subjects.

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection - a long way to go.

Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size.

Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects.

Aim: Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure.

Pharmacokinetics and pharmacodynamics of orally administered clonidine: a model-based approach.

Background/aims: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test.

Post-burn hypertrophic scars are characterized by high levels of IL-1β mRNA and protein and TNF-α type I receptors.

Post-burn hypertrophic scars are characterized by increased collagen synthesis and hyperplasia, and may be associated with erythema, pain, dysesthesia, pruritus, and skin border elevation. Although the etiopathogenesis of hypertrophic scarring remains unclear, proinflammatory and profibrogenic cytokines are known to play an important role in general skin dysfunction. This study assessed mRNA expression, proteins, and type I receptors of tumor necrosis factor-alpha (TNF-α) and interleukin 1-beta (IL-1β) in normal skin, normotrophic and post-burn hypertrophic scars.