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Exposure to combustion-derived air pollution is associated with an early (1-2 h) and sustained (24 h) rise in cardiovascular morbidity and mortality. We have previously demonstrated that inhalation of diesel exhaust causes an immediate (within 2 h) impairment of vascular and endothelial function in humans. To investigate the vascular and systemic effects of diesel exhaust in humans 24 hours after inhalation. Fifteen healthy men were exposed to diesel exhaust (particulate concentration, 300 microg/m(3)) or filtered air for 1 hour in a double-blind, randomized, crossover study. Twenty-four hours after exposure, bilateral forearm blood flow, and inflammatory and fibrinolytic markers were measured before and during unilateral intrabrachial bradykinin (100-1,000 pmol/min), acetylcholine (5-20 microg/min), sodium nitroprusside (2-8 microg/min), and verapamil (10-100 microg/min) infusions. Resting forearm blood flow, blood pressure, and basal fibrinolytic markers were similar 24 hours after either exposure. Diesel exhaust increased plasma cytokine concentrations (tumor necrosis factor-alpha and interleukin-6, p < 0.05 for both) but appeared to reduce acetylcholine (p = 0.01), and bradykinin (p = 0.08) induced forearm vasodilatation. In contrast, there were no differences in either endothelium-independent (sodium nitroprusside and verapamil) vasodilatation or bradykinin-induced acute plasma tissue plasminogen activator release. Twenty-four hours after diesel exposure, there is a selective and persistent impairment of endothelium-dependent vasodilatation that occurs in the presence of mild systemic inflammation. These findings suggest that combustion-derived air pollution may have important systemic and adverse vascular effects for at least 24 hours after exposure.

Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. The goal of this study was to investigate potential drug–drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. The potential drug–drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2–5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2–5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5. Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0–∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87–107.20; Cmax: GMR, 92.39%; 90% CI, 85.38–99.97) or ramipril (AUC over a uniform dosing interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05–100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65–111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% CI 100.51–116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73–119.64) or its active metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00–101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67–104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0–∞ (GMR, 106.11%; 90% CI, 96.71–116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33–130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation in any of the studies. No dose adjustment of empagliflozin is required when coadministered with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril).

Background Lovastatin is an inhibitor of P-glycoprotein (P-gp) and is metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. Verapamil is a substrate of both P-gp and CYP3A4. It is therefore likely that lovastatin can alter the absorption and metabolism of verapamil. Methods The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared in 14 healthy male Korean volunteers (age range 22-28 years) who had been administered verapamil (60 mg) orally in the presence or absence of oral lovastatin (20 mg). The design of the experiment was a standard 2 × 2 crossover model in random order. Results The pharmacokinetic parameters of verapamil were significantly altered by the co-administration of lovastatin compared to the control. The area under the plasma concentration-time curve [graphic removed] and the peak plasma concentration of verapamil were significantly increased by 62.8 and 32.1%, respectively. Consequently, the relative bioavailability of verapamil was also significantly increased (by 76.5%). The [graphic removed] of norverapamil and the terminal half-life of verapamil did not significantly changed with lovastatin coadministration. The metabolite-parent ratio was significantly reduced (29.2%) in the presence of lovastatin. Conclusion Lovastatin increased the absorption of verapamil by inhibiting P-gp and inhibited the first-pass metabolism of verapamil by inhibiting CYP3A4 in the intestine and/or liver in humans.

Background and Objective In microdose studies, the pharmacokinetic profile of a drug in blood after administration of a dose up to 100μg is measured with sensitive analytical techniques, such as accelerator mass spectrometry (AMS). As most drugs exert their effect in tissue rather than blood, methodology is needed for extending pharmacokinetic analysis to different tissue compartments. In the present study, we combined, for the first time, AMS analysis with positron emission tomography (PET) in order to determine the pharmacokinetic profile of the model drug verapamil in plasma and brain of humans. In order to assess pharmacokinetic dose linearity of verapamil, data were acquired and compared after administration of an intravenous microdose and after an intravenous microdose administered concomitantly with an oral therapeutic dose. Methods Six healthy male subjects received an intravenous microdose [0.05 mg] (period 1) and an intravenous microdose administered concomitantly with an oral therapeutic dose [80 mg] of verapamil (period 2) in a randomized, crossover, two-period study design. The intravenous dose was a mixture of ( R/S )-[ 14 C] verapamil and ( R )-[ 11 C]verapamil and the oral dose was unlabelled racaemic verapamil. Brain distribution of radioactivity was measured with PET whereas plasma pharmacokinetics of ( R )- and ( S )-verapamil were determined with AMS. PET data were analysed by pharmacokinetic modelling to estimate the rate constants for transfer (k) of radioactivity across the blood-brain barrier. Results Most pharmacokinetic parameters of ( R )- and ( S )-verapamil as well as parameters describing exchange of radioactivity between plasma and brain (influx rate constant [K 1 ] =0.030 ±0.003 and 0.031±0.005 mL/ mL/min and efflux rate constant [k 2 ] = 0.099 ± 0.006 and 0.095 ± 0.008 min−1 for period 1 and 2, respectively) were not statistically different between the two periods although there was a trend for nonlinear pharmacokinetics for the ( R )-enantiomer. On the other hand, all pharmacokinetic parameters (except for the terminal elimination half-life [t 1/2 ]) differed significantly between the ( R )- and ( S )-enantiomers for both periods. The maximum plasma concentration (C max ), area under the plasma concentration-time curve (AUC) from 0 to 24 hours (AUC 24 ) and AUC from time zero to infinity (AUC ∞ ) were higher and the total clearance (CL), volume of distribution (V d ) and volume of distribution at steady state (V ss ) were lower for the ( R )- than for the ( S )-enantiomer. Conclusion Combining AMS and PET microdosing allows long-term pharmacokinetic data along with information on drug tissue distribution to be acquired in the same subjects thus making it a promising approach to maximize data output from a single clinical study.

To characterise the comparative potency of optically pure (R)- and (S)-verapamil as regards negative dromotropic effects on atrioventricular (AV) node conduction and to compare the hemodynamic effects of single doses of the enantiomers in healthy volunteers. Eight healthy volunteers received a single oral dose of 120 mg (S)-verapamil, 480 mg (R)-verapamil, 240 mg racemic verapamil (rac-verapamil) or placebo on 4 separate occasions. Serum concentrations of (R)- and (S)-verapamil were measured up to 24 h. Cardiovascular effects were assessed by electrocardiography, measurement of blood pressure and transthoracic impedance cardiography (cardiac output and total peripheral resistance). The comparative potency of (R)- and (S)-verapamil with regard to prolongation of the PR interval in the surface ECG was estimated by use of the areas under the effect-time and serum concentration-time curves and linear regression analyses of per cent change in PR interval from baseline versus the logarithm of serum (R)- or (S)-verapamil concentration. The PR interval was significantly prolonged after all verapamil treatments as compared with placebo. (S)-verapamil was 20.6-21.8 times more potent than (R)-verapamil with regard to negative dromotropic effects. (R)-verapamil caused a significantly greater maximum reduction in the mean arterial pressure (MAP) than placebo [15.9+/-6.8 versus 8.7+/-3.2 mmHg (mean+/-SD); 95% CI on the difference, 0.79-13.7 mmHg; p<0.05], whereas MAP was not affected by the other verapamil treatments. No significant changes were observed in heart rate, cardiac output and total peripheral resistance after any verapamil treatment as compared with placebo. (S)-verapamil was about 20 times more potent than (R)-verapamil with regard to negative dromotropic effects on AV node conduction. (R)-verapamil but not (S)-verapamil significantly reduced the MAP as compared with placebo.

Human gut wall cytochrome P(450) (CYP)3A4 is inhibited by grapefruit juice (G), whereas smoking increases CYP1A2 activity. Both enzymes contribute to verapamil biotransformation. This study was performed to quantitatively assess the effect of these factors on verapamil pharmacokinetics in steady state. Twenty-four young healthy volunteers of both sexes (12 smokers, 12 non-smokers) participated in this randomised crossover study. Prolonged release verapamil (120 mg, Isoptin KHK) was given bid for 7 days in two periods. During days 5-7, 1 l of either G or water was coadministered daily. On day 7, concentrations of verapamil and norverapamil enantiomers were determined during one dosing interval, and model independent pharmacokinetic parameters were estimated. PR intervals were monitored for pharmacodynamics. Statistical evaluation was done essentially using bioequivalence methods. G significantly increased ( R, S)-verapamil the area under the concentration-time curve at steady state (AUC(tau,ss)) by a mean of 1.45-fold [90% confidence interval (CI) 1.29, 1.63] and peak plasma concentration at steady state (C(max,ss)) by 1.63-fold (90% CI 1.38, 1.91). The increase in concentrations present for ( R)- and ( S)-enantiomers was slightly greater for verapamil than for norverapamil. Smokers had significantly lower AUC(tau,ss) and C(max,ss) values than non-smokers by (means) 0.61-fold to 0.85-fold for verapamil and norverapamil enantiomers, respectively. G effects were unrelated to naringenin pharmacokinetics. Prolongation of PR intervals by G coadministration was borderline significant; an increase above 350 ms occurred in two individuals during the G period. Significantly increased urinary 6-beta-hydroxycortisol excretion by G suggests induction of hepatic CYP3A. Patients on verapamil treatment should abstain from grapefruit juice. Smoking habits should be considered for verapamil dosing.

A novel, fast and sensitive enantioselective HPLC assay with a new core–shell isopropyl carbamate cyclofructan 6 (superficially porous particle, SPP) chiral column (LarihcShell-P, LSP) was developed and validated for the enantiomeric separation and quantification of verapamil (VER) in rat plasma. The polar organic mobile phase composed of acetonitrile/methanol/trifluoroacetic acid/triethylamine (98:2:0.05: 0.025, v/v/v/v) and a flow rate of 0.5 mL/min was applied. Fluorescence detection set at excitation/emission wavelengths 280/313 nm was used and the whole analysis process was within 3.5 min, which is 10-fold lower than the previous reported HPLC methods in the literature. Propranolol was selected as the internal standard. The S-(−)- and R-(+)-VER enantiomers with the IS were extracted from rat plasma by utilizing Waters Oasis HLB C18 solid phase extraction cartridges without interference from endogenous compounds. The developed assay was validated following the US-FDA guidelines over the concentration range of 1–450 ng/mL (r2 ≥ 0.997) for each enantiomer (plasma) and the lower limit of quantification was 1 ng/mL for both isomers. The intra- and inter-day precisions were not more than 11.6% and the recoveries of S-(−)- and R-(+)-VER at all quality control levels ranged from 92.3% to 98.2%. The developed approach was successfully applied to the stereoselective pharmacokinetic study of VER enantiomers after oral administration of 10 mg/kg racemic VER to Wistar rats. It was found that S-(−)-VER established higher Cmax and area under the concentration-time curve (AUC) values than the R-(+)-enantiomer. The newly developed approach is the first chiral HPLC for the enantiomeric separation and quantification of verapamil utilizing a core–shell isopropyl carbamate cyclofructan 6 chiral column in rat plasma within 3.5 min after solid phase extraction (SPE).

Therapeutic drug monitoring (TDM) is necessary for the optimal administration of anti-arrhythmic drugs in the treatment of heart arrhythmia. The present study aimed to develop and validate a direct analysis in real time tandem mass spectrometry (DART–MS/MS) method for the rapid and simultaneous determination of five anti-arrhythmic drugs (metoprolol, diltiazem, amiodarone, propafenone, and verapamil) and one metabolite (5-hydroxy(OH)-propafenone) in human serum. After the addition of isotope-labeled internal standards and protein precipitation with acetonitrile, anti-arrhythmic drugs were ionized by DART in positive mode followed by multiple reaction monitoring (MRM) detection. The use of DART–MS/MS avoided the need for chromatographic separation and allowed rapid and ultrahigh throughput analysis of anti-arrhythmic drugs in a total run time of 30 s per sample. The DART–MS/MS method yielded satisfactory linearity (R 2  ≥ 0.9906), accuracy (86.1–109.9%), and precision (≤ 14.3%) with minimal effect of biological matrixes. The method was successfully applied to analyzing 30 clinical TDM samples. The relative error (RE) of the concentrations obtained by DART–MS/MS and liquid chromatography-tandem mass spectrometry (LC–MS/MS) was within ± 13%. This work highlights the potential usefulness of DART for the rapid quantitative analysis of anti-arrhythmic drugs in human serum and gives rapid feedback in the clinical TDM practices.

For revealing the peculiarities of the drug–drug interaction of rivaroxaban (substrate CYP3A4 and P-gp) and calcium channel blockers (CCBs) (verapamil – inhibitor CYP3A4 and P-gp and amlodipine – substrate CYP3A4) in patients 80 years and older with nonvalvular atrial fibrillation (NAF) we studied 128 patients.All patients were divided into groups depending on the therapy taken: the 1st – rivaroxaban + amlodipine (n=51), the 2nd – rivaroxaban + verapamil (n=30), the control group – rivaroxaban without CCBs (n=47). A trough steady-state plasma concentration (Cmin,ss) of rivaroxaban, prothrombin time (PT) in the blood plasma and the event of clinically relevant non-major (CRNM) bleeding were assessed for each patient.Patient in group 2 had higher Cmin,ss of rivaroxaban, PT and CRNM than subjects in the control group (Me 73.8 [50.6–108.8] ng/mL vs. 40.5 [25.6–74.3] ng/mL; Me 14.8 [13.4–17.3] s vs. 13.8 [12.6–14.4] s; 34% vs. 13%, respectively, p<0.05 for all). When compared, the PT and complication rate in group 1 with the control group Cmin,ss of rivaroxaban were practically the same (p>0.05 for all).In patients ≥80 years with NAF, the use of rivaroxaban in combination with verapamil may not be safe and can lead to CRNM bleeding.

Tozadenant is one of the selective adenosine A2a receptor antagonists with a potential to be a new Parkinson’s disease (PD) therapeutic drug. In this study, a liquid chromatography-mass spectrometry based bioanalytical method was qualified and applied for the quantitative analysis of tozadenant in rat plasma. A good calibration curve was observed in the range from 1.01 to 2200 ng/mL for tozadenant using a quadratic regression. In vitro and preclinical in vivo pharmacokinetic (PK) properties of tozadenant were studied through the developed bioanalytical methods, and human PK profiles were predicted using physiologically based pharmacokinetic (PBPK) modeling based on these values. The PBPK model was initially optimized using in vitro and in vivo PK data obtained by intravenous administration at a dose of 1 mg/kg in rats. Other in vivo PK data in rats were used to validate the PBPK model. The human PK of tozadenant after oral administration at a dose of 240 mg was simulated by using an optimized and validated PBPK model. The predicted human PK parameters and profiles were similar to the observed clinical data. As a result, optimized PBPK model could reasonably predict the PK in human.