Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers.

BACKGROUND: Four-factor prothrombin complex concentrates (PCCs), which contain factor II, FVII, FIX, and FX, have shown the potential to reverse the anticoagulant effect of rivaroxaban in healthy volunteers. The purpose of this study was to determine whether a three-factor PCC, which contains little FVII, has a similar effect. METHODS AND RESULTS: We performed an open-label, single-center, parallel-group study comparing the effect of a three-factor PCC (Profilnine SD) with that of a four-factor PCC (Beriplex P/N) on the pharmacodynamics of rivaroxaban in 35 healthy volunteers. After receiving 4 days of rivaroxaban 20 mg twice daily to obtain supratherapeutic steady-state concentrations, volunteers were randomized to receive a single 50 IU kg(-1) bolus dose of four-factor PCC, three-factor PCC or saline 4 h after the morning dose of rivaroxaban on day 5, and the effects of these interventions on prothrombin time and thrombin generation were determined. Within 30 min, four-factor PCC reduced mean prothrombin time by 2.5-3.5 s, whereas three-factor PCC produced only a 0.6-1.0-s reduction. In contrast, three-factor PCC reversed rivaroxaban-induced changes in thrombin generation more than four-factor PCC. CONCLUSIONS: This study demonstrates the potential of both three-factor and four-factor PCCs to at least partially reverse the anticoagulant effects of rivaroxaban in healthy adults. The discrepant effects of the PCC preparations may reflect differences in the procoagulant components present in each.

Pharmacokinetics of fluvoxamine maleate after increasing single oral doses in healthy subjects.

The pharmacokinetics of fluvoxamine after single oral administration of 25, 50, and 100 mg fluvoxamine maleate was studied in a three-way cross-over study in 12 healthy male subjects. Fluvoxamine was administered orally in a solution. For dose-proportionality, AUC, and Cmax-dose relationships were evaluated by linear regression. Plasma concentrations increased in a linear dose-dependent manner in the dose range between 25 and 100 mg; t1/2 and Tmax showed no significant differences among treatments. Fluvoxamine was well tolerated.

Pharmacokinetics of fluvoxamine maleate in patients with liver cirrhosis after single-dose oral administration.

The pharmacokinetics of fluvoxamine maleate were investigated in 13 patients with biopsy-proven liver cirrhosis. They received a single oral 100mg dose as an enteric-coated tablet, and plasma samples were collected up to 168h after administration. Geometric mean values for peak plasma concentrations and area under the plasma concentration-time curves (AUC) were 39 micrograms/L and 1338 micrograms.h/L, respectively. Mean (+/- SD) elimination half-life (t1/2) was 25 +/- 11h, and increased with higher plasma bilirubin levels, although no relationship between bilirubin and AUC was observed. AUC was about 50% higher in patients than in healthy volunteers from another similar study. This was mainly because of a longer t1/2. Although there is a great overlap between AUC values of fluvoxamine in patients and healthy volunteers, it is nevertheless concluded that in patients with signs of active liver disease, e.g. raised bilirubin, it is wise to lower the initial daily dose and to carefully monitor the patient during subsequent upward dose adjustments.

Single and multiple oral dose fluvoxamine kinetics in young and elderly subjects.

The pharmacokinetics of fluvoxamine maleate was studied in two separate studies in healthy young and elderly subjects. In a single and multiple oral dose administration study, six healthy young subjects received an initial 50 mg oral dose followed by 50 mg tablets every 12 h for 28 days. In a second study, 13 elderly subjects received 50 mg tablets every 12 h for 28 days. Fluvoxamine peak plasma concentrations were reached in approximately 5-6 h following oral administration of single and multiple 50 mg doses to healthy young and elderly volunteers. The area under the curve (AUC) of fluvoxamine tended to be larger following multiple (873 ng.h/ml) as compared to single-dose administration (652 ng.h/ml). Also the terminal half-life after chronic dosing (22 +/- 6 h) tended to be longer than after single dosing. Steady-state plasma levels were obtained within 10 days' administration. The pharmacokinetics of fluvoxamine in elderly healthy subjects were no different from those recorded in young subjects. These results suggest that it is not necessary to adjust the dosage of fluvoxamine in elderly depressed patients, on the basis of pharmacokinetic arguments. Independent of the age group, approximately 3% of a dose was recovered as unchanged drug in the urine.

Fluvoxamine does not interact with alcohol or potentiate alcohol-related impairment of cognitive function.

OBJECTIVE: To assess whether fluvoxamine alters the pharmacokinetics of alcohol or potentiates alcohol-related impairment of cognitive function. METHODS: The study design required partially "blinded" balanced crossover studies, each involving 12 healthy male volunteers who each received a 40 gm dose of intravenous or oral alcohol after single and multiple doses of 50 mg fluvoxamine. Main outcome measures for pharmacokinetics were venous blood alcohol and plasma fluvoxamine. Main outcome measures for pharmacodynamics were word recall, simple and choice reaction time, number vigilance, memory scanning, and word recognition. RESULTS: The pharmacokinetics of intravenous alcohol were not affected by concomitant administration of fluvoxamine. Compared with placebo-alcohol, alcohol slightly increased the rate of fluvoxamine absorption, but the area under the plasma concentration-time curve from 0 to 12 hours at steady state was unchanged. As expected, alcohol significantly impaired cognitive function in volunteers. However, fluvoxamine did not potentiate the effects of alcohol and in some instances appeared to reverse the effects or reduce their duration. Fluvoxamine was well tolerated: only mild adverse effects were reported, and none of those required intervention. CONCLUSION: Fluvoxamine does not interact significantly with alcohol or potentiate alcohol-related impairment of cognitive function.

Bioavailability of fluvoxamine given with and without food.

The influence of concomitant food intake on plasma concentrations of the antidepressant drug fluvoxamine maleate was investigated in a two-way, crossover study design. Eight male and four female healthy, young volunteers received a single oral dose of fluvoxamine maleate (50 mg, tablet) on two occasions: after an overnight fast and immediately after a breakfast. Food did not affect maximum fluvoxamine plasma levels (Cmax), or the time to reach Cmax (tmax). The plasma AUC of fluvoxamine was on average 7 per cent lower in the fed than in the fasted state. It is concluded that the effect of food on the pharmacokinetics of fluvoxamine is negligible.

Kinetics of acetaminophen after single- and multiple-dose oral administration as a gradient matrix system to healthy male subjects.

The in vivo characteristics of two formulations of a recently developed controlled-release system, the Gradient Matrix System (GMS-1 and GMS-2), with acetaminophen as a model drug compound have been determined in healthy volunteers both after separate single- and multiple-dose administration. Values for the mean residence time (MRT) were increased from 5.2 h for an oral solution to 10.2 and 13.3 h for two GMS formulations after single dosing. Peak plasma concentrations were lower for the two GMS formulations after single dosing compared to the oral solution. The bioavailability, relative to the oral solution, was 91 per cent and 84 per cent for the two GMS formulations tested. After multiple dosing of one of the GMS formulations over 5 days, no change in AUC compared to the single dose AUC occurred. Steady state was reached within 2-3 days of twice daily dosing of the GMS formulation. The peak-trough-fluctuation (per cent PTF) was 44 per cent. No signs of dose dumping were observed in fasted subjects. A plateau-like plasma drug concentration profile at steady state was maintained with the GMS formulation.

Comparison of in vitro and in vivo release characteristics of acetaminophen from gradient matrix systems.

An effort was made to correlate the in vivo and in vitro release data of acetaminophen from two formulations of a recently developed controlled-release system, the Gradient Matrix System (GMS-1 and GMS-2). The in vivo release curves, obtained by deconvolution of the plasma concentration time plots, showed a small inter-subject variability. GMS-1 with fastest in vitro release also showed fastest in vivo release. A good relationship was only found after time-scaling of the release data.

Dose-proportionality of eltoprazine. Pharmacokinetics of single oral doses in healthy subjects.

Eltoprazine. HCl belongs to a new class of psychotropic drug, the serenics. The dose-proportionality and pharmacokinetics of eltoprazine HCl has been investigated after single oral doses of 5, 10, 20 mg (18 subjects) and 30 mg (12 subjects) in a partly randomized, cross-over design. Eltoprazine was well tolerated and there were no relevant changes in safety parameters. All subjects showed irregular plasma-concentration-time profiles, some subjects demonstrating secondary peaks. The mean half-life was calculated to be about 6.5 h. The renal excretion of eltoprazine was characterized by net tubular secretion. AUC, peak plasma concentrations and the amount excreted unchanged in the urine were linearly related to the dose. Renal clearance and t1/2 were independent of dose. Thus, eltoprazine HCl was well tolerated orally and exhibited a linear pharmacokinetic profile.

Kinetics of idaverine in healthy male subjects after single dose oral and intravenous administration.

The kinetics of idaverine was studied in an open, cross-over, partially randomized design after single oral (2 mg) and intravenous (1 and 2 mg doses to 12 healthy male subjects. In the first session, the volunteers were administered 1 mg idaverine by constant intravenous infusion during 45 min. The treatments in the second and third sessions were given according to a cross-over design, randomized in blocks of six for each session (2 mg either orally or by intravenous infusion during 45 min). The washout period between the sessions was at least 1 week. Plasma, urine and faeces were analysed for idaverine and its pharmacologically active metabolite N-desmethylidaverine by gas chromatography with nitrogen flame ionisation detection. After intravenous administration, the MRT was on average 2 hours and the mean CLS was about 900 ml.min-1. CLR is about twice the glomerular filtration rate, suggesting net tubular secretion of idaverine. The AUC and the cumulative urinary and faecal excretion values gave no indication of dose-disproportionality within the range of 1 and 2 mg administered intravenously. Maximum plasma levels of 1-3 ng.ml-1 were reached between 0.5 hours and 3 hours after oral dosing. The MRT was 4.4 hours. Systemic availability was about 29%. N-desmethylidaverine was barely detectable in plasma after all doses. Idaverine was well tolerated, only a small increase in heart rate was observed.

Pharmacokinetics of eltoprazine in healthy male subjects after single dose oral and intravenous administration.

The kinetics, safety and tolerability of eltoprazine hydrochloride were studied in an open, cross-over, partially randomised design after single oral (8 mg) and intravenous (3 and 8 mg) doses to 12 healthy male subjects. After intravenous administration, the mean t1/2 ranged from 7 to 9 h, the MRT was 11 h, CL was 487 +/- 148 (3 mg dose) and 471 +/- 56 (8 mg dose) ml kg-1 h-1, while CLR was 226 +/- 124 (3 mg dose) and 189 +/- 38 (8 mg dose) ml kg-1 h-1. The Vss was 3.3 +/- 0.7 (3 mg dose) and 3.8 +/- 0.5 (8 mg dose) 1 kg-1. Cumulative renal excretion was 40%. The AUC and the cumulative urinary excretion were directly proportional to dose within the range of 3-8 mg. Values of tmax varied from 1 to 4 h after oral administration. The mean Cmax value was 24 ng ml-1 after an oral dose of 8 mg. The plasma elimination half-life after oral administration was 9.8 +/- 3.9 h. Absolute oral bioavailability was 110 +/- 32%. Dose-dependent somnolence was observed.

Ethopharmacology: a creative approach to identification and characterisation of novel psychotropics.

The present contribution describes the basic fundamentals of animal models in ethopharmacology. After defining the role of ethopharmacology in the development of animal models of relevant human diseases, this methodology is used to classify different categories of aggression. Furthermore, the behavioural aspects of agonistic (aggressive) modelling are outlined and the various models used to describe offensive and defensive behaviours, and some miscellaneous models are summarized. Finally, some remarks on the new class of psychoactive drugs, serenics, are given.

Distribution of radioactively labelled eltoprazine in rat and dog.

Eltoprazine labelled with 14C either in the phenyl or the piperazine ring was administered orally to rats and dogs. While distribution of radioactivity was not affected by the position of label during the first hours after dosing, from six hours onward concentrations of radioactivity in the organs of rats were higher after [14C]piperazine-labelled eltoprazine. In most organs, radioactivity originating from the [14C]phenyl-labelled compound was detectable up to 72 hours, while [14C]piperazine-labelled material could still be detected 384 hours after dosing. These results suggest that the piperazine ring may be broken down to aliphatic amines which are retained in the body. Quantitatively, however, this is of minor importance, representing about 1% of the dose. With either label, the highest concentrations of the radiolabel were found in liver and kidney. Excretion of radioactivity in rat and dog urine and faeces was not influenced by the position of the radiolabel.

The metabolite patterns of eltoprazine in man, dog, rat and rabbit.

To compare the metabolism of eltoprazine of dog, rat and rabbit with that in man, urine samples were collected after dosing with 14C-eltoprazine. The 14C-labelled metabolites were separated by chromatography and detected by their radioactivity. This resulted in so-called metabolite patterns. The human metabolite pattern contained peaks that were all found in that obtained from the dog's urine. The dog's metabolite pattern had two peaks that were (almost) absent in all other species. The rat's urine gave a pattern which had only two peaks in common with the human pattern. Unchanged drug was excreted in significant amounts by man, dog, and rat, but not by rabbit. This excretion was even a little more pronounced after intravenous injection of the drug. In man, the ratio between unchanged drug and metabolites was fairly constant with time after dosing, while this ratio decreased in the animal species. The major part of the metabolites were sulphate- or glucuronide conjugates, but hydrolysis of these required extraordinary amounts of enzyme. We do not yet know whether the observed species differences reflect differences in conjugating activity or (and) oxidative metabolism. We could not identify important differences in the metabolite patterns that were due to sex or route of drug administration. Also, the site of the 14C-label in the drug molecule hardly affected the metabolite patterns; the only effect was the excretion by the rat of a very polar but minor component when it was dosed with 14C-piperazine labelled eltoprazine. This component was absent when 14C-phenyl labelled eltoprazine was given.

Pharmacokinetics of eltoprazine in healthy subjects.

The pharmacokinetics of eltoprazine in healthy male subjects was investigated after intravenous and oral dosing in one study, and after oral dosing of 14C-eltoprazine in a second study. It was shown that the absorption of eltoprazine from the gastro-intestinal tract was complete, and that absolute bioavailability was 100%. The mean elimination half-life of eltoprazine in plasma was about 8 hours. Approximately 40% of the dose was excreted unchanged in urine.

The polymorphonuclear leukocyte: its pharmacological transport and target properties: an overview.

The need for experimental models to study cellular pharmacokinetics and mechanisms of cell association of drugs in relation to the (patho)physiology is obvious. These models, although never identical to the in vivo physiological environment, can provide fundamental insights with respect to cellular transport mechanisms of drugs in vivo. This knowledge contributes to the development of drug targeting. The human polymorphonuclear leukocyte (PMN) was chosen in our studies as model and target cell because of its involvement in the action of different groups of drugs. First, the physiology and transport characteristics of the PMN has been described. Secondly, the mechanisms of association of some drugs with the PMN are considered. The possible contribution of cellular pharmacokinetics to drug targeting to the PMN is discussed.

Modes of association of indometacin with human polymorphonuclear leucocytes.

The basic transport properties of indometacin (INDO) were investigated in human blood polymorphonuclear leucocytes (PMNs) of healthy volunteers. The silicone oil cushion centrifugation method was used as ligand-binding assay for both the measurements of the cellular association of INDO and the intracellular volume. This assay enabled us to calculate the intracellular INDO concentrations. A considerable amount of INDO accumulates in the PMNs to cause cell/medium ratios between 20 and 90. At low INDO levels (1-10 nmol/l) the cell/medium ratio appeared to be higher than at high INDO levels (greater than 2 mumol/l). This finding suggests that the cell accumulation of INDO comprises saturable binding and/or transport components. Scatchard analysis of the association isotherm of INDO after incubation for 60 min at 37 degrees C reveals apparent KD values of 3.7 mumol/l (low affinity) and 1.2 nmol/l (high affinity). The number of high-affinity association sites (60 fmol/3 X 10(6) PMNs) was 1,000-2,000 times lower than the number of low-affinity association sites (103 pmol/3 X 10(6) PMNs). INDO cell association is suggested to be a net result of diffusive and mediated influx and efflux mechanisms, and of binding to (plasma) membranes. The capacity of the PMN to accumulate INDO is enhanced upon (1) establishment of an inward gradient of [H+], and (2) activation of the Na(+)-H+ antiport by chemotactic peptide. The possible mechanisms of incorporation of INDO in the PMN are discussed in the scope of the proposed PMN-related anti-inflammatory action of INDO.