Pharmacokinetic-pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects.

What Is Already Known About This Subject: • The cholinergic system is important for different central nervous system functions, including memory, learning and attention. Scopolamine, a centrally active muscarinic antagonist, has been used to model dementia and to demonstrate the pharmacological effects of cholinergic drugs, but for most effects the concentration-effect relationships are unknown.

What This Study Adds: • We determined the pharmacokinetic-pharmacodynamic relationships of scopolamine using a multidimensional central nervous system test battery in a large group of healthy volunteers.

Central nervous system effects of alcohol at a pseudo-steady-state concentration using alcohol clamping in healthy volunteers.

Aim: In determining the acute effects of alcohol, it is helpful if alcohol concentrations are maintained at stable levels, to facilitate the interpretation of the results. Recently, an alcohol clamping method was developed that resulted in stable alcohol concentrations for hours. The aim of this study was to test a range of central nervous system (CNS) effects under pseudo-steady-state conditions.

Clinically important interaction between tedisamil and verapamil.

Tedisamil, a class III antiarrhythmic drug, is a P-glycoprotein substrate. Tedisamil treatment may implicate coadministration with class IV antiarrhythmics such as verapamil, a P-glycoprotein inhibitor. Pharmacokinetic and pharmacodynamic interactions between tedisamil and verapamil were evaluated in a double-blind, crossover study.

A comparative study of two methods for attaining constant alcohol levels.

Aims: Alcohol effects or drug-alcohol interactions are preferably studied at constant blood levels. To achieve pseudo-steady state levels, various methods are used, which usually produce adequate averages but variable individual concentration profiles. The aim was to compare two modes of alcohol administration: a 'two-step prekinetic procedure' and a 'clamping method'.

Autonomic nervous system function in chronic exogenous subclinical thyrotoxicosis and the effect of restoring euthyroidism.

Context: Knowledge on the relationship between the autonomic nervous system and subclinical hyperthyroidism is mainly based upon cross-sectional studies in heterogeneous patient populations, and the effect of restoration to euthyroidism in subclinical hyperthyroidism has not been studied.

Objective: We investigated the long-term effects of exogenous subclinical hyperthyroidism on the autonomic nervous system and the potential effects of restoration of euthyroidism.

Design: This was a prospective single-blinded, placebo-controlled, randomized trial.

Effect of garlic powder on C-reactive protein and plasma lipids in overweight and smoking subjects.

Background: Epidemiologic studies suggest that garlic may have beneficial effects on risk factors associated with cardiovascular disease (CVD). However, these findings are not unambiguously supported by randomized placebo-controlled clinical trials.

Objective: We sought to investigate the effects of a chemically well-characterized garlic preparation on biomarkers for inflammation, endothelial function, and lipid metabolism in subjects with risk factors for CVD.

Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat.

Background: The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form.

A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema.

Background: Hereditary angioedema (HAE) is a congenital disorder with recurrent attacks of localized swelling of submucosal tissue, subcutaneous tissue, or both caused by a deficiency of the plasma protein C1 inhibitor (C1 esterase inhibitor [C1INH]).

Objective: We sought to evaluate the effects of recombinant human C1INH (rhC1INH) isolated from the milk of transgenic rabbits in 12 asymptomatic patients with HAE.

Methods: rhC1INH was intravenously administered at doses of 6.

AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients.

Background: Tacrolimus has a narrow therapeutic window, and bioavailability is known to vary considerably between renal transplant recipients. Most centers still rely on measurement of trough levels, but there are conflicting reports on the correlation between tacrolimus trough levels and systemic exposure, as measured by the area-under-the-concentration-over-time curve (AUC((0-12h))).

Methods: We developed and validated a two-compartmental population-based pharmacokinetic model with Bayesian estimation of tacrolimus systemic exposure.

Relationship between airway responsiveness to neurokinin A and methacholine in asthma.

Non-adrenergic non-cholinergic (NANC) nerves release bronchoactive tachykinins such as substance P (SP) and neurokinin A (NKA) that can induce features of asthma. The airway response to NKA in humans closely resembles that of methacholine (M). Hence, we investigated the relationship between airway responsiveness to NKA and M in subjects with asthma.

Pharmacokinetics of oral fumarates in healthy subjects.

Aims: To characterize the pharmacokinetics of fumarates in healthy subjects.

Methods: Ten subjects received a single fumarate tablet (containing 120 mg of dimethylfumarate and 95 mg of calcium-monoethylfumarate) in the fasted state and after a standardized breakfast in randomized order. Prior to and at fixed intervals after the dose, blood samples were drawn and the concentrations of monomethylfumarate, the biologically active metabolite, as well as dimethylfumarate and fumaric acid were measured using high-performance liquid chromatography.

Effects of a nonpeptide motilin receptor antagonist on proximal gastric motor function.

Aim: To assess the effects of the motilin receptor antagonist RWJ-68023 on basal and motilin-stimulated proximal gastric volume.

Methods: Eighteen healthy male volunteers received RWJ-68023 in two different doses or placebo for 135 min. After 45 min, subjects received a motilin infusion for 90 min.

Central nervous system effects of moxonidine experimental sustained release formulation in patients with mild to moderate essential hypertension.

Objectives: The primary aim was to demonstrate that moxonidine, given in an experimental sustained release (SR) formulation, had no clinically relevant central nervous system (CNS) effects after 4 weeks of treatment. A clinically relevant CNS effect was predefined as more than 45 degrees s-1 reduction in saccadic peak velocity (SPV), corresponding to the effects of one night's sleep deprivation.

Methods: In a randomized, double-blind fashion, 35 patients with mild to moderate essential hypertension received placebo run-in medication for 2 weeks, followed by 4 weeks' moxonidine sustained release (1.

Endothelial binding of recombinant tissue plasminogen activator: quantification in vivo using a recirculatory model.

Binding of tissue plasminogen activator (t-PA) to the endothelium may be important in the prevention of thrombus formation. The aim was to develop a method to quantify endothelial binding in vivo. Nine healthy male volunteers received a 40 min continuous infusion with low dose recombinant t-PA (3.

A compartmental pharmacokinetic model of cyclosporin and its predictive performance after Bayesian estimation in kidney and simultaneous pancreas-kidney transplant recipients.

Background: Therapeutic drug monitoring of cyclosporin A (CsA) is an obvious necessity because of its unpredictable absorption and narrow therapeutic window. The use of limited sampling models (LSMs) has improved the estimation of the systemic exposure [area under curve (AUC)] compared with C(0h) monitoring, but these equations are rigid and not reliable in patients with an abnormal absorption profile. We developed and validated a limited sampling (t=0, 2 and 3 h) strategy, based on a compartmental population pharmacokinetic (PK) model for CsA after kidney transplantation alone (KTA) and simultaneous pancreas-kidney transplant (SPKT) recipients, a group of patients with unpredictable absorption kinetics.

Local tissue factor pathway inhibitor release in the human forearm.

Nineteen healthy men received unilateral brachial artery infusions of either unfractioned heparin (0.3-100 IU/min), saline or the endothelium-dependent vasodilators substance P (2-8 pmol/min) and bradykinin (100-1000 pmol/min), and the endothelium-independent vasodilator sodium nitroprusside (2-8 micro g/min). Heparin caused a dose-dependent increase in plasma TFPI concentrations in both arms (ANOVA, p <0.

Motilin effects on the proximal stomach in patients with functional dyspepsia and healthy volunteers.

This study investigates motilin effects on the proximal stomach in patients with functional dyspepsia (FD) and healthy volunteers. Eight healthy volunteers and 12 patients with FD were infused with synthetic motilin or placebo. Proximal gastric volume was measured with a barostat at constant pressure and during isobaric distensions.

Quantification of heparin-induced TFPI release: a maximum release at low heparin dose.

Aims: Heparin releases tissue factor pathway inhibitor (TFPI) from the endothelium and this release may decrease after repeated high dose heparin administration. The primary aim was to investigate and quantify this phenomenon during a short low dose heparin infusion. Also, the effects of heparin on tissue plasminogen activator (t-PA) were studied.

Saccadic peak velocity and EEG as end-points for a serotonergic challenge test.

Unlabelled: We previously reported that a single dose of the serotonin receptor agonist meta-chlorophenylpiperazine increased the peak velocity of saccadic eye movements and decreased low-frequency electroencephalographic activity.

Methods: We administered a single dose of the serotonin releaser dexfenfluramine in a double blind, placebo controlled randomised cross-over design and measured saccadic eye movements and EEG every hour up to 6 h. Subjects were 62 males (18-30 years) with a history of no, moderate or heavy use of ecstasy tablets.

Estimation of plasma serotonin using isopycnic centrifugation.

The valid measurement of the concentration of serotonin (5-HT) in blood plasma is important when using the platelet as a model for the serotonergic neuron. The assay is hampered by the release of 5-HT by (residual) platelets during the preparation for assay. We developed an isopycnic method that separates cells gently and completely from plasma by centrifuging a diluted Percoll density-gradient to which whole blood was added.

Concentration-effect relationships of two rilmenidine single-dose infusion rates in hypertensive patients.

Objectives: This study was designed to assess the concentration-effect relationships for the antihypertensive effects of rilmenidine in patients to aid in the design of an optimized concentration profile of a sustained-release formulation.

Methods: A placebo-controlled, randomized, double-blind, 2-way partial crossover study was performed in subjects with hypertension. Patients were randomized to receive 2 of 3 possible 12-hour infusion regimens, each consisting of a loading phase (2 hours) and a maintenance phase (10 hours): low-profile infusion (total dose of rilmenidine, 1.

Development of an optimal furosemide infusion strategy in infants with modeling and simulation.

Background: The optimal dosing strategy for continuous intravenous furosemide infusion is unknown in pediatric patients. Eighteen patients less than 1 year old were studied after cardiac surgery during routine clinical care. The current strategy starts with a continuous infusion of 0.

Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers.

Objective: Patients undergoing major orthopaedic surgery who are being treated with fondaparinux sodium for prevention of venous thromboembolism may be receiving treatment for coronary artery disease or chronic inflammatory disease of the joints or arthritis. Two separate studies assessed any possible interaction between fondaparinux sodium at steady state and aspirin (acetylsalicylic acid) or piroxicam in healthy volunteers.

Design: In the first study a single dose of aspirin 975mg was assessed initially, followed by single doses of aspirin or placebo on the fourth day of an 8-day regimen of subcutaneous fondaparinux sodium (10mg once daily).

Modeling the influence of growth hormone on lipolysis.

Lipolysis (the breakdown of fat) is generally estimated using stable isotopes, where the rate of appearance (Ra) of glycerol is calculated using Steele's equations. These equations are based on single-compartment differential equations for tracer and tracee where rate of change is approximated by the change in concentration from one time point to the next. We demonstrate an alternative approach to estimate metabolic processes, and to determine relationships between hormones and their actions.