Search

Objectives: The aim of this study was to compare the efficacy of a dentifrice without sodium lauryl sulfate (SLS) to a dentifrice with SLS in young adults aged 18-34 years on gingivitis., Material and Methods: One hundred twenty participants (non-dental students) with a moderate gingival inflammation (bleeding on probing at 40-70 % of test sites) were included in this randomized controlled double blind clinical trial. According to randomization, participants had to brush their teeth either with dentifrice without SLS or with SLS for 8 weeks. The primary outcome was bleeding on marginal probing (BOMP). The secondary outcomes were plaque scores and gingival abrasion scores (GA) as well as a visual analogue scale (VAS) score at exit survey. Baseline and end differences were analysed by univariate analysis of covariance (ANCOVA) test, between group differences by independent t test and within groups by paired sample t test., Results: BOMP improved within groups from on average 0.80 at baseline to 0.60 in the group without SLS and to 0.56 in the group with SLS. No statistical difference for BOMP, plaque and gingival abrasion was found between both groups. VAS scores for taste, freshness and foaming effect were significantly in favour of the SLS-containing dentifrice., Conclusion: The test dentifrice without SLS was as effective as a regular SLS dentifrice on gingival bleeding scores and plaque scores. There was no significant difference in the incidence of gingival abrasion., Clinical Relevance: In patients diagnosed with gingivitis, a dentifrice without SLS seems to be equally effective compared to a dentifrice with SLS and did not demonstrate any significant difference in gingival abrasion. In patient with recurrent aphthous ulcers, the absence of SLS may even be beneficial. However, participants indicate that they appreciate the foaming effect of a dentifrice with SLS more.

Aim: To assess the effect of protein-containing toothpastes on the progression of dental erosion in situ (with pellicle) and in vitro (without pellicle)., Methods: A combined split-mouth (extraoral water or toothpaste brushing) and crossover (type of toothpaste) setup was used. Two protein-containing (high/low concentrations of colostrum) and one nonprotein (placebo) toothpaste were investigated. Sixteen volunteers wore intraoral appliances containing 2 human enamel samples on 3 afternoons for pellicle growth during 90 min. One enamel sample was brushed for 5 s with one of the three toothpastes and subsequently exposed to a slurry of the corresponding toothpaste for 2 min. The other sample was exposed to water. Both samples were subsequently exposed to citric acid (extraorally). Loss of calcium and inorganic phosphate were determined. The same sequence of exposures was applied to 16 enamel samples in an in vitro setup without pellicle., Results: With the in situ-formed pellicle, all toothpastes significantly reduced calcium loss compared to water brushing, although no significant differences were found among toothpastes (p = 0.073). For the loss of phosphate, a significant reduction could be found with the use of the high-protein toothpaste compared to the nonprotein toothpaste. Overall there were only slight differences between the toothpastes. Toothpaste effects were less clear in the in vitro experiment., Conclusion: The addition of proteins to toothpaste shows some promise for the prevention of erosion. Further research is needed to investigate the performance of the protein-containing toothpastes in longer in situ studies with regard to erosive wear., (Copyright © 2012 S. Karger AG, Basel.)

Bovine whey protein products are used as a base ingredient in infant formulas to optimize the amino acid pattern to a more human-like composition. Although the protein composition of bovine milk has been studied in detail, glycosylation details of commercial whey protein products are missing. To this end, both the N- and O-glycans of such a protein concentrate were sequentially released, the N-glycans enzymatically and the O-glycans chemically (reducing and nonreducing conditions). For the structural analysis of the N- and O-glycans a combination of MALDI-TOF-MS, one-dimensional (1)H NMR spectroscopy, Wisteria floribunda agglutinin affinity chromatography, HPAEC-PAD profiling, and HPLC-FD profiling (2-aminobenzamide derivatives), together with exoglycosidase treatments, were used. A mixture of over 60 N-glycans and 10 O-glycans was characterized, giving a detailed insight into the glycosylation of a bovine whey protein product, Deminal 90, which is applied as an ingredient for infant formulas.

Background: Over the years, the N-glycosylation of both human and bovine lactoferrin (LF) has been studied extensively, however not all aspects have been studied in as much detail. Typically, the bovine LF complex-type N-glycans include certain epitopes, not found in human LF N-glycans, i.e. Gal(α1-3)Gal(β1-4)GlcNAc (αGal), GalNAc(β1-4)GlcNAc (LacdiNAc), and N-glycolylneuraminic acid (Neu5Gc). The combined presence of complex-type N-glycans, with αGal, LacdiNAc, LacNAc [Gal(β1-4)GlcNAc], Neu5Ac (N-acetylneuraminic acid), and Neu5Gc epitopes, and oligomannose-type N-glycans complicates the high-throughput analysis of such N-glycoprofiles highly., Methods: For the structural analysis of enzymatically released N-glycan pools, containing both LacNAc and LacdiNAc epitopes, a prefractionation protocol based on Wisteria floribunda agglutinin affinity chromatography was developed. The sub pools were analysed by MALDI-TOF-MS and HPLC-FD profiling, including sequential exoglycosidase treatments., Results: This protocol separates the N-glycan pool into three sub pools, with (1) free of LacdiNAc epitopes, (2) containing LacdiNAc epitopes, partially shielded by sialic acid, and (3) containing LacdiNAc epitopes, without shielding by sialic acid. Structural analysis by MALDI-TOF-MS and HPLC-FD showed a complex pattern of oligomannose-, hybrid-, and complex-type di-antennary structures, both with, and without LacdiNAc, αGal and sialic acid., Conclusions: Applying the approach to bovine LF has led to a more detailed N-glycome pattern, including LacdiNAc, αGal, and Neu5Gc epitopes, than was shown in previous studies., General Significance: Bovine milk proteins contain glycosylation patterns that are absent in human milk proteins; particularly, the LacdiNAc epitope is abundant. Analysis of bovine milk serum proteins is therefore excessively complicated. The presented sub fractionation protocol allows a thorough analysis of the full scope of bovine milk protein glycosylation. This article is part of a Special Issue entitled Glycoproteomics., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Levels of nonsulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from six ovariectomized, mature female cynomolgus monkeys after a single dose and multiple p.o. doses (including bile) of tibolone using validated gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry assays. In plasma, the predominant nonsulfated metabolite after single and multiple dosing was the estrogenic 3alpha-hydroxytibolone; levels of the estrogenic 3beta-hydroxytibolone were 10-fold lower and of progestagenic/androgenic Delta(4)-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone; levels of 3betaS,17betaS-tibolone were about 2-fold lower, and monosulfated 3-hydroxymetabolites were about 10-fold lower. After multiple doses, areas under the curve of nonsulfated metabolites were lower (2-fold), and those of sulfated metabolites were 25% higher. In plasma, >95% metabolites were disulfated. In urine, levels of all the metabolites after single and multiple doses were low. After a single dose, high levels of 3beta-hydroxytibolone and the 3-monosulfated metabolites (3betaS,17betaOH-tibolone and 3alphaS,17betaOH-tibolone) were found in feces. After multiple dosing, 3alpha-hydroxytibolone increased, and the ratio of 3alpha/3beta-hydroxytibolone became about 1. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone. Levels of all the metabolites in feces were higher after multiple doses than after a single dose. Levels of nonsulfated and 3-monosulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except monosulfates. This may contribute to the metabolite content of the feces after multiple doses. 3beta-Hydroxytibolone and 3alphaS,17betaS-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces, and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. The major excretion route was in feces.

The objective of this study was to determine pharmacokinetic parameters of sulfated tibolone metabolites after single dose and their accumulation after multiple doses of tibolone. Blood samples from postmenopausal women in a single-dose (2.5 mg tibolone), open-label study (n=8) and multiple-dose (placebo, 0.3, 0.625, 1.25, or 2.5 mg/day tibolone for twenty-six cycles of 28 days), randomized, double-blind study (n=15) were analyzed for non-sulfated and sulfated tibolone metabolites by validated gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with tanolam mass spectrometry (LC-MS/MS), respectively. The predominant non-sulfated and sulfated metabolites after a single dose were 3alpha-hydroxy-tibolone and 3alpha,17beta-di-sulfated (di-S)-tibolone. At 3 h, >90% of metabolites were sulfated. Tibolone and Delta(4)-tibolone were detectable for about 6 h. After multiple treatment cycles with different doses, metabolite levels at 10 h were dose-related and levels of di-S metabolites were three- to fivefold higher than after a single dose. Tibolone metabolite levels did not differ between cycles. Inactive di-S tibolone metabolites predominated in blood. No accumulation occurred between cycles 7 and 26.

Background: The new antidepressant gepirone acts preferentially on 5-hydroxytryptamine type 1A (5-HT1A) receptors and functions as a 5-HT1A agonist. Placebo-controlled clinical studies have established that gepirone has a good safety profile and is effective for the treatment of depression. A previous study showed that administration of gepirone immediate release 15 minutes after a meal instead of during a fast increased the mean area under the plasma concentration-time curve (AUC) by 37%. Gepirone was reformulated into extended release (ER), which necessitated further exploration of the effects of food on bioavailability., Objective: This article describes 2 studies of the pharmacokinetic properties of gepirone ER and 1 of its metabolites, 1(2-pyrimidinyl)-piperazine (1-PP), in healthy subjects. In study 1, we assessed the effects of food and the influence of time of food intake relative to dosing on the bioavailability of gepirone ER. The objective of study 2 was to confirm that gepirone ER has similar pharmacokinetic characteristics under fed and fasting conditions., Methods: Two open-label, randomized, single-dose, crossover studies balanced for first-order residual effects were conducted to assess the bioavailability of gepirone from ER tablets. Healthy male subjects received a 20-mg oral dose of gepirone ER. In study 1, subjects took the gepirone ER dose after a 10-hour overnight fast or 1 hour before, 15 minutes after, or 2 hours after a standard high-fat meal. In study 2, subjects either took the gepirone ER dose after a 10-hour overnight fast and continued to fast for 4 more hours or took the gepirone ER dose 15 minutes after a standard high-fat meal., Results: Twenty-eight men (mean [SD] age, 27.2 [6.6] years) participated in study 1, and 27 men (mean [SD] age, 31.8 [9.6] years) participated in study 2. In study 1, the mean (SD) maximum peak plasma concentration (Cmax) for gepirone ER was 69.2% higher (3.25 [1.71] vs 1.92 [0.96] ng/mL) (P≤0.05) and the AUC from time 0 to 30 hours for gepirone ER was 31.9% higher (39.3 [20.6] vs 29.8 [15.3] ng/mL·h) (P≤0.05) for the 15-minute postprandial dose than for the fasting dose, respectively. In study 2, the mean Cmax for gepirone was 62.0% higher (4.13 vs 2.55 ng/mL) and the mean AUC from time 0 to infinity for gepirone was 24% higher (38.71 vs 31.14 ng/mL·h) for the postprandial dose than for the fasting dose (P<0.05). All reported adverse effects were mild to moderate in intensity, and most (study 1) or all (study 2) occurred during the fasting state., Conclusions: When administered with food, the bioavailability (AUC and Cmax) of gepirone ER was greater than during the fasting state, with the greatest bioavailability seen when the drug was taken 15 minutes after eating. Based on this pharmacokinetic analysis, it may be prudent to administer gepirone ER consistently, either always with or always without food.

In an open-label, randomized, crossover study, the pharmacokinetics of gepirone immediate-release (gepirone-IR) and different gepirone extended-release (gepirone-ER, types 1, 2, and 3) formulations were compared. Mean maximum concentration (C(max)) was 6.1 ng/mL for gepirone-IR, which was statistically significantly (p < 0.05) higher than that of two of the ER-formulations (3.7 and 3.6 ng/mL, respectively, for types 2 and 3). The mean time to C(max) (mean T(max)) was 1.3 h for gepirone-IR and ranged from 4.8 to 5.6 h for gepirone-ER. The mean area under the curve of concentration versus time (AUC(30)) was similar and not statistically significantly different between gepirone-IR and ER. For the 1-(2-pyrimidinyl)-piperazine (1-PP) metabolite, C(max) and AUC(30) were statistically significantly (p < 0.05) higher and T(max) was lower for gepirone-IR compared with ER. No significant differences in bioavailability were observed between the IR and the three gepirone-ER formulations, indicating that any of the once-daily gepirone-ER formulations could be substituted for gepirone-IR. This study revealed a reduction in the peak-to-trough fluctuations in plasma gepirone concentrations and maintenance of consistent plasma levels with gepirone-ER., (Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association)

Objective: To assess the steady-state pharmacokinetics of mirtazapine (30 mg/day orally) and amitriptyline (75 mg/day orally) during combined administration compared with that of either drug administered alone. To evaluate the tolerability and effects on psychometric tests of acute and subchronic administration of both drugs combined and alone., Methods: In a single-blind, three-way cross-over study, 24 (12 male and 12 female) healthy subjects were randomly assigned to six different sequences of three 9-day treatments, i.e. racemic mirtazapine (30 mg/day), amitriptyline (75 mg/day) or the combination of these drugs. To control for acute pharmacodynamic assessments, during the first treatment period, a placebo group (n = 8; 4 females and 4 males) was added. Serial blood samples were drawn for plasma level measurements that were subsequently subjected to pharmacokinetic analysis. Psychometric tests assessed attentional performance, and a computer-assisted telephone questionnaire assessed self-ratings of drowsiness/alertness and sleep quality., Results: Amitriptyline increased the C(max) of mirtazapine (+ 36%, p < 0.05) in male subjects only. Mirtazapine altered the C(max) of amitriptyline in both male (+ 23%, p < 0.05) and female (- 23%, p < 0.05) subjects. No changes were observed for other pharmacokinetic parameters. Metabolite parameters were not affected. Changes in parent compound levels mainly resulted from effects on absorption. The psychometric test results did not reveal significant changes between combined and single drug treatments. The telephone registrations of VAMRS and LSEQ did not show clinically relevant differences between the active treatments., Conclusion: Combined administration of mirtazapine (30 mg/day) and amitriptyline (75 mg/day) alters the pharmacokinetics of either compound to a minor extent. Adding one drug to the other and substituting one drug by the other had no major effects on tolerability. Nevertheless, caution is warranted when combining amitriptyline and mirtazapine., (Copyright 2003 John Wiley & Sons, Ltd.)

Aims: Tibolone is a tissue-specific compound with favourable effects on bone, vagina, climacteric symptoms, mood and sexual well being in postmenopausal women, without stimulating the endometrium or breast. Since tibolone is used for the treatment of both young and elderly postmenopausal women, its pharmacokinetics were studied to investigate potential differences with age. In addition, the bioequivalence of the 1.25 and 2.5 mg tablets was evaluated., Methods: Single doses of 1.25 or 2.5 mg of tibolone were given in a double-blind, randomized, two-way cross-over study to women aged between 45 and 55 years or between 65 and 75 years of age., Results: Age did not have a significant effect on C(max), t(max), and t(1/2) of tibolone and its metabolites and on the body weight standardized oral clearance (CL/F kg(-1)) of the 3alpha- and 3beta-hydroxy tibolones. In early postmenopausal women, significantly lower values were found for the AUC(0,16 h), and AUC(0, infinity ) of 3alpha-hydroxy tibolone 24.6+/-6.6 vs 29.2+/-4.9 and 27.1+/-6.9 vs 32.3+/-6.5 ng ml(-1) h for the 1.25 mg tablet, respectively, and 45.4+/-13.9 vs 55.7+/-14.1 and 49.6+/-14.6 vs 62.6+/-17.3 ng ml-1 h for the 2.5 mg tablet, respectively. When these values were adjusted for the significantly higher body weight of the early postmenopausal women, the differences disappeared. No significant differences between early and late postmenopausal women were found for the AUC(0,8 h), and AUC(0, infinity) of 3beta-hydroxy tibolone. The rate of absorption of tibolone and the rates of absorption or formation of the 3alpha- and 3beta-hydroxy tibolones were significantly higher after the 1.25 mg dose than after the 2.5 mg tablet, resulting in increases of 32%, 27% and 17% for the dose normalized-C(max) of tibolone and the 3alpha- and 3beta-hydroxy tibolones, respectively. tmax for tibolone and its metabolites was 12-27% less after 1.25 mg compared to 2.5 mg, which was statistically significant. The two formulations were bioequivalent with respect to the dose-normalized AUC(0, infinity) and the AUC(0,t(fix)) values for the 3alpha-hydroxy tibolone (ratio point estimate [90%, confidence limits]: 1.08 [1.04, 1.14] and 1.08 [1.03, 1.13], respectively) and for the 3beta-hydroxy tibolone (1.07 [1.01, 1.14] and 1.04 [0.96, 1.12], respectively). Both formulations were also bioequivalent with respect to CL/F kg(-1) and t(1/2)., Conclusions: The pharmacokinetics of tibolone are similar in early (age 45-55 years) and late (65-75 years) postmenopausal women. The 2.5 and 1.25 mg tablets are bioequivalent with respect to the extent of absorption. The rate of absorption or formation of the metabolites of tibolone were not bioequivalent, but these differences are considered to have no clinical relevance in view of the chronic administration of tibolone.

Study Objective: To assess the effect of food on absorption and pharmacokinetic disposition of tibolone., Design: Open-label, randomized, crossover study with a 1-week washout period., Setting: Institut für Klinische Pharmakologie, Hohenkirchen-Siegertsbrunn, Germany, Subjects: Twenty-four healthy, early postmenopausal women., Intervention: Single doses of tibolone 2.5 mg were administered after subjects consumed a high-fat meal or fasted., Measurements and Main Results: Plasma concentrations of tibolone and its three primary metabolites, delta4-tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone, were assayed by gas chromatography with mass spectrometry. Peak plasma concentration (Cmax), time to Cmax, area under the plasma concentration versus time curve from time zero to infinity (AUC(0-infinity)), and elimination half-life were calculated, and food effects were evaluated. Plasma concentrations of tibolone and delta4-tibolone were too low to estimate AUC(0-infinity) and half-life. Absorption or formation of 3alpha-hydroxytibolone and 3beta-hydroxytibolone was slower in fed participants than in fasting participants, but this was of no clinical relevance because of the long-term nature of tibolone treatment. Meal consumption did not affect AUC(0-infinity) or half-life for 3alpha-hydroxytibolone and 3beta-hydroxytibolone., Conclusion: Food consumption decreased and delayed Cmax but had no effect on the exposure of tibolone and its metabolites. Tibolone therefore can be administered irrespective of meal timing.

Study Objective: To determine the influence of renal function on the pharmacokinetics of tibolone and its primary metabolites, delta4-tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone., Design: Open-label, single-center, single-dose study, Setting: Drug research center, Balatonfüred, Hungary., Subjects: Twenty-four postmenopausal women aged 45-65 years., Intervention: Subjects were assigned to one of four groups based on their renal function, as assessed by glomerular filtration rate (normal to severely impaired), and received a single dose of tibolone 2.5 mg. Pharmacokinetic parameters of tibolone and its primary metabolites were derived from blood samples taken at predefined intervals for up to 48 hours after tibolone administration. Pharmacokinetic parameters were calculated using standard noncompartmental methods and compared by analysis of covariance., Measurements and Main Results: Pharmacokinetic parameters of tibolone and its primary metabolites were similar in subjects with normal to severely impaired renal function. Pharmacokinetic profiles of tibolone and its metabolites were independent of the degree of renal impairment., Conclusion: Pharmacokinetic parameters of tibolone were not affected by varying degrees of renal function.

Study Objective: To assess dose proportionality of tibolone tablets after multiple oral administration., Design: Open-label, randomized, three-period crossover study, Setting: Department of Drug Metabolism and Kinetics, N.V. Organon, Oss, The Netherlands., Subjects: Twenty-seven postmenopausal women aged 65 years or younger., Intervention: Subjects received tibolone 1.25, 2.5, or 5.0 mg once/day for 7 days., Measurements and Main Results: Plasma concentrations of tibolone and its three primary metabolites were assayed. Steady state was attained by day 5. Elimination half-life for 3alpha-hydroxytibolone was 7.2-8.5 hours. At steady state, the dose-normalized peak concentration and area under the curve satisfied bioequivalence requirements for the 1.25- and 2.5-mg doses, but not fully for the 5.0-mg dose. Parameters were proportionally slightly lower for the 5.0-mg dose compared with the 1.25- and 2.5-mg doses., Conclusion: Proportional bioequivalence was established for the 1.25- and 2.5-mg doses, but not between the 5.0-mg dose and the two lower doses of tibolone.

Objective: To assess the pharmacokinetics of etonogestrel and ethinylestradiol released from a novel combined contraceptive vaginal ring (NuvaRing) releasing etonogestrel 120microg and ethinylestradiol 15 microg per day and compare them with those of a combined oral contraceptive containing desogestrel 150 microg/ethinylestradiol 30 microg (DSG/EE COC)., Design and Setting: This was a nonblind, randomised, crossover study in 16 healthy women., Methods: All volunteers received one cycle of DSG/EE COC before being randomised to 1 of 2 treatment groups. The participants in group 1 received 1 cycle of DSG/EE COC, a treatment period with NuvaRing and an intravenous bolus injection of etonogestrel/ethinylestradiol (150 microg/30 microg). Those in group 2 received a NuvaRing treatment period, 1 cycle of DSG/EE COC and the same intravenous bolus injection., Results and Conclusions: After the insertion of NuvaRing, maximum serum concentrations of etonogestrel and ethinylestradiol were achieved in approximately 1 week. The concentrations subsequently showed a gradual linear decrease in time. The maximum serum concentrations of etonogestrel and ethinylestradiol were approximately 40 and 30%, respectively, of those for the DSG/EE COC. In comparison with the DSG/EE COC, the absolute bioavailability for NuvaRing was higher for etonogestrel (102.9 vs 79.2%) and similar for ethinylestradiol (55.6 vs 53.8%). Taking the difference in daily doses into account, systemic exposure to etonogestrel was similar for NuvaRing and the DSG/EE COC, whereas systemic exposure to ethinylestradiol with NuvaRing was only approximately 50% of that for the DSG/EE COC.

Objective: The objective of this study was to examine the pharmacokinetics and the tolerability/safety of mirtazapine and cimetidine separately and in combination following oral administration of multiple doses., Methods: This was a double-blind, placebo-controlled, two-period cross-over, multiple-dose pharmacokinetic interaction study in 12 healthy male subjects. They received either cimetidine (800 mg b.i.d.) or placebo in combination with (commercially available, racemic) mirtazapine (30 mg nocte). Cimetidine and placebo were administered for 14 days, with mirtazapine added during days 6-12 of each period. Serial blood samples for kinetic profiling were taken on day 5 and day 12 for cimetidine and on days 12-14 for mirtazapine., Results: The co-administration of cimetidine resulted in a statistically significant increase in the area under the curve (AUC(0-24)) and Cmax of mirtazapine (54% and 22% respectively). The AUC(0-24) of demethylmirtazapine increased only slightly, and there was no effect on Cmax. The elimination half-lives for both mirtazapine and its demethyl metabolite were unaffected by cimetidine co-administration. The trough and average plasma concentrations during the steady state were elevated during cimetidine treatment (62% and 54%, respectively). Mirtazapine had no effect on the pharmacokinetics of cimetidine., Conclusion: Co-administration of cimetidine (800 mg b.i.d.) and mirtazapine (30 mg nocte) resulted in increased steady-state plasma levels of mirtazapine (C(ss,min) = +61%, P < 0.05; C(ss,av) = +54%, P < 0.05), probably as a result of increased bio-availability. The Cmax (+22%, P < 0.05) and AUC(0-24) (+54%, P < 0.05) also increased. Due to the variability of the mirtazapine plasma levels in patients, the clinical meaning of these increases is probably limited. Co-administration of mirtazapine did not alter cimetidine pharmacokinetics.

A substantial proportion of patients diagnosed with depression and treated with antidepressants show no or insufficient response. In such patients, lithium is often added to the antidepressant for augmentation. The present study investigated the possible drug-drug interaction between mirtazapine and lithium in 12 healthy male subjects in a randomized, double-blind, placebo-controlled two-period cross-over design. Subjects meeting the inclusion and exclusion criteria were randomly assigned to one of two groups. After an overnight fast, they received either a single oral dose of 600 mg lithium carbonate (16 meq Li+) for 10 days at 08.00 h and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9 or the same number (n = 4) of placebo capsules and and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9. At pre-defined times, blood samples were drawn for the measurement of mirtazapine plasma concentrations and lithium serum concentrations. In addition, psychometric tests were performed and the safety and tolerability of the drugs were assessed. The results indicate that mirtazapine does not alter the pharmacokinetics of lithium and vice versa. In addition, the combination of mirtazapine and lithium appeared to be safe and well-tolerated. Extensive psychometric testing after the administration of mirtazapine did not reveal any differences on any tests in subjects on lithium and placebo, respectively.

Mirtazapine is the first noradrenergic and specific serotonergic antidepressant ('NaSSA'). It is rapidly and well absorbed from the gastrointestinal tract after single and multiple oral administration, and peak plasma concentrations are reached within 2 hours. Mirtazapine binds to plasma proteins (85%) in a nonspecific and reversible way. The absolute bioavailability is approximately 50%, mainly because of gut wall and hepatic first-pass metabolism. Mirtazapine shows linear pharmacokinetics over a dose range of 15 to 80mg. The presence of food has a minor effect on the rate, but does not affect the extent, of absorption. The pharmacokinetics of mirtazapine are dependent on gender and age: females and the elderly show higher plasma concentrations than males and young adults. The elimination half-life of mirtazapine ranges from 20 to 40 hours, which is in agreement with the time to reach steady state (4 to 6 days). Total body clearance as determined from intravenous administration to young males amounts to 31 L/h. Liver and moderate renal impairment cause an approximately 30% decrease in oral mirtazapine clearance; severe renal impairment causes a 50% decrease in clearance. There were no clinically or statistically significant differences between poor (PM) and extensive (EM) metabolisers of debrisoquine [a cytochrome P450 (CYP) 2D6 substrate] with regard to the pharmacokinetics of the racemate. The pharmacokinetics of mirtazapine appears to be enantioselective, resulting in higher plasma concentrations and longer half-life of the (R)-(-)-enantiomer (18.0 +/-2.5h) compared with that of the (S)-(+)-enantiomer (9.9+/-3. lh). Genetic CYP2D6 polymorphism has different effects on the enantiomers. For the (R)-(-)-enantiomer there are no differences between EM and PM for any of the kinetic parameters; for (S)-(+)-mirtazapine the area under the concentration-time curve (AUC) is 79% larger in PM than in EM, and a corresponding longer half-life was found. Approximately 100% of the orally administered dose is excreted via urine and faeces within 4 days. Biotransformation is mainly mediated by the CYP2D6 and CYP3A4 isoenzymes. Inhibitors of these isoenzymes, such as paroxetine and fluoxetine, cause modestly increased mirtazapine plasma concentrations (17 and 32%, respectively) without leading to clinically relevant consequences. Enzyme induction by carbamazepine causes a considerable decrease (60%) in mirtazapine plasma concentrations. Mirtazapine has little inhibitory effects on CYP isoenzymes and, therefore, the pharmacokinetics of coadministered drugs are hardly affected by mirtazapine. Although no concentration-effect relationship could be established, it was found that with therapeutic dosages of mirtazapine (15 to 45 mg/day), plasma concentrations range on average from 5 to 100 microg/L.

Objective: To assess the dose-proportionality and pharmacodynamic properties of multiple doses of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands)., Design: Randomized, parallel, pharmacokinetic, and pharmacodynamic study., Setting: Phase I clinical research unit., Patient(s): Three groups of 15 healthy female volunteers of reproductive age., Intervention(s): Subcutaneous injections of 0.125 mg, 0.25 mg, or 0.50 mg of ganirelix were given once daily for 7 days. Blood samples were taken to assess serum ganirelix, LH, FSH, and E2 concentrations., Main Outcome Measure(s): Pharmacokinetic parameters and hormone suppression., Result(s): Steady-state levels were reached between days 2 and 3. Peak concentrations, which occurred approximately 1 hour after dosing, increased in a dose-proportional manner and averaged 5.2 ng/mL, 11.2 ng/mL, and 22.2 ng/mL for the 0.125-mg, 0.25-mg, and 0.50-mg doses, respectively. Corresponding mean values for the area under the curve over one dosing interval (24 hours) were 33 ng x h/mL, 77.1 ng x h/mL, and 137.8 ng x h/mL, respectively. After the last 0.25-mg dose of ganirelix, serum LH, FSH, and E2 concentrations were maximally decreased (by 74%, 32%, and 25% at 4 hours, 16 hours, and 16 hours after injection, respectively). Serum hormone levels returned to pretreatment values within 2 days after the last injection., Conclusion(s): The pharmacokinetics of ganirelix were dose-proportional within the dose range studied. Multiple injections resulted in immediate suppression of gonadotropins, which was rapidly reversed after treatment discontinuation.

Objective: To assess the absolute bioavailability of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands) after a single SC injection., Design: Randomized, crossover, pharmacokinetic study., Setting: Phase I clinical research unit., Patient(s): Nineteen healthy female volunteers of reproductive age., Intervention(s): Two separate injections of 0.25 mg of ganirelix were given, one subcutaneously and one intravenously, with a washout period of 1 week between injections. Blood samples were taken for assessment of serum ganirelix concentrations, and blood pressure, heart rate, and adverse events were monitored., Main Outcome Measure(s): Pharmacokinetic parameters., Result(s): Fifteen subjects were evaluated. The mean concentration-time profile after SC administration was comparable to that after IV administration. The mean (+/- SD) peak concentration and time of occurrence after SC administration were 14.8+/-3.2 ng/mL and 1.1+/-0.3 hours, respectively. The mean (+/- SD) half-lives after IV administration and SC administration were highly similar (12.7+/-3.7 hours and 12.8+/-4.3 hours, respectively). Mean (+/- SD) AUC0-infinity (area under the concentration-time curve) values of 105+/-11 ng/mL x hours and 96+/-12 ng/mL x hours were calculated for IV administration and SC administration, respectively, resulting in an absolute mean (+/- SD) bioavailability of 91.3%+/-6.7%. Both treatments were well tolerated., Conclusion(s): Ganirelix is absorbed rapidly and extensively after SC administration, resulting in a high absolute bioavailability of >90%.

In a three-period cross-over study with 24 healthy young females (study part 1), the bioavailability of etonogestrel (3-ketodesogestrel) was determined after a single oral dose of two Cerazette tablets (each containing 75 microg desogestrel), one Liseta tablet (containing 150 microg desogestrel and 1.5 mg 17beta-estradiol), and an intravenous dose of 150 microg etonogestrel. Etonogestrel serum levels from 23 subjects could be analysed by radio-immunoassay. The geometric mean bioavailability of etonogestrel from Cerazette and Liseta tablets was 0.79 and 0.82, with 95% confidence intervals of 0.73-0.86 and 0.76-0.88, respectively. Also, the oral formulations were found to be bioequivalent. Subsequently, the single-dose pharmacokinetic parameters of etonogestrel from Cerazette tablets were compared with those after multiple dosing of one Cerazette tablet once daily for 7 days, in a subgroup of 12 subjects (study part 2). A steady state was observed from the fourth day of daily dosing onwards, with time-invariant parameters except for a 14% lower dose-normalised AUC. The least-squares geometric means of the elimination half-life of etonogestrel were approximately 30 h for the three single-dose treatments in study part 1, as well as for the single- and multiple-dose treatments of Cerazette in study part 2, without differences between groups.

Objective: The aim of the study was to assess the bioavailability of estradiol (E2) following oral, single-dose administration of equimolar doses of three HRT preparations in a 3-way cross-over study in postmenopausal women., Methods: 18 healthy subjects were enrolled. Free E2 and estrone (E1) serum concentrations were determined using commercially available immunoassay kits. Bioequivalence testing was performed between the following oral formulations: (a) 1.5 mg E2 tablets versus 2 mg E2V tablets; and (b) 1.5 mg E2 plus 0.15 mg DSG tablets versus 1.5 mg E2 tablets., Results: For both E2 and E1 the E2 tablet was bioequivalent with both the E2V and the E2/DSG tablet with respect to the rate and extent of absorption (bioavailability). Although the mean tmax values of the three tablet formulations were similar, the variability was too large to prove formal bioequivalence., Conclusion: E2 tablets and E2/DSG tablets were bioequivalent and also bioequivalence of E2 tablets with commercially available E2V was found, which ensures a sequential HRT preparation without large variations in estrogen serum concentrations.

The pharmacokinetics and enterohepatic cycling of oestradiol have been studied after three oral, single-dose administrations of equimolar doses of oestradiol alone, oestradiol plus desogestrel and oestradiol valerate, in a 3-way cross-over mode in 18 healthy postmenopausal women. Oestradiol was readily absorbed and metabolized to oestrone, which reached much higher serum concentrations (140pgmL(-1)) than its parent compound (35pgmL(-1)). All three formulations had the same kinetic profile and were bioequivalent on testing. Noticeable first and second absorption phases were apparent from the oestradiol and oestrone serum concentration-time curves for all oestradiol formulations. The mean serum concentration-time curves of the metabolite oestrone (corrected for endogenous oestrone) showed a second maximum at approximately 25h. By means of line feathering, serum concentration-time curves were constructed which belonged to the first, second and third phases of absorption. The maximum serum concentration, Cmax, of the second absorption or recirculation of oestrone was 20% that of the first, and the Cmax of the third circulation was 50% that of the second. The areas under the serum-concentration-time curves (AUC) for the second and third recirculations were similar-each comprised 12-13% of the total AUC. The oral clearance values of the recirculations were constant (590Lh(-1)). Enterohepatic recirculation of endogenous compounds is aimed at maintaining a steady-state serum concentration for immediate use and hydrolysis in the target organs. It is concluded that exogenously added oestradiol and its metabolites follow the recirculation pathways of the endogenous oestrogen pool.

The purpose of the present study was to establish in vitro the inhibiting effect of a herbal extract mixture on a selected number of micro-organisms and to test in vivo the effect of a mouthwash containing 6.3 mg/ml herbal extract mixture on plaque and gingivitis as compared to a minus active control mouthrinse. The herbal extract was a mixture of: Juniperus communis (juniper), Urtica dioca (nettle), Achillaea millefolium (yarrow); 1:1:1. In the study, in-vitro, the effect of pure herbal extract mixture on acid production of Streptococcus mutans was tested and the minimum inhibitory concentrations (MIC) of the following micro-organisms were tested: Streptococcus mutans, Streptococcus mitis, Actynomyces viscosus, Actynomyces naeslundii, Actinobacillus actinomycetemcomitans, Prevotella intermedia, Campylobacter rectus, Fusobacterium nucleatum, Veillonella parvula. The MIC-values for A. viscosus and P. gingivalis were 100 mg/ml. The MIC-values for A. naeslundii and A. actinomycetemcomitans were considerably lower (10 mg/ml). S. mitis was the most susceptible of the tested organisms to the extract with a MIC value of 1 mg/ml. S. mutans, C. rectus, V. parvula, and F. nucleatum were not influenced by the extracts. No inhibitory effect of the 6.3 mg/ml herbal extract mixture was observed on the acid production of S. mutans. For the study in-vivo, 45 volunteers were selected on the basis of having moderate gingival inflammation. As efficacy parameters the plaque index, modified gingival index and angulated bleeding index were assessed. The subjects were randomly divided among 3 experimental groups (2x test and 1 'minus active' control). The participants were requested to rinse with 10 ml of mouthwash twice a day for a period of three months. After 6 weeks and 3 months, the same clinical indices as at baseline were recorded. The results show no difference between the two test groups and the control group. In conclusion, the results of the present study have shown that the mixture of the 3 herbal extracts, Juniperus communis, Urtica dioca and Achillaea millefolium when used in a mouthrinse has no effect on plaque growth and gingival health.

This paper investigated the pharmacokinetics and biotransformation of mirtazapine in healthy human volunteers. The results showed that the area under the plasma drug concentration-time curve (AUC) of mirtazapine in human plasma appeared to be three times higher than the AUC of demethylmirtazapine. As mirtazapine is marketed as a racemic mixture and both enantiomers possess pharmacological properties essential for the overall activity of the racemate, the pharmacokinetics of mirtazapine were examined and appeared to be enantioselective. The R(-)-enantiomer showed the longest elimination half-life from plasma. This was ascribed to the preferred formation of a quaternary ammonium glucuronide of the R(-)-enantiomer. This glucuronide may be deconjugated, leading to a further circulation of the parent compound, thus causing a prolongation in the elimination half-life. The S(+)-enantiomer was preferentially metabolised into an 8-hydroxy glucuronide. Other metabolic transformation pathways found for mirtazapine were demethylation and N-oxidation. Mirtazapine was extensively metabolised and almost completely excreted in the urine (over 80%) and faeces within a few days after oral administration.

The effect of a high-fat meal on the pharmacokinetics of mirtazapine was studied in 19 healthy normal young male volunteers. In a randomized two-period crossover study, each volunteer received an oral dose of 15 mg of mirtazapine in the form of tablets, in the fasting state and after a high-fat meal, with a washout period of 14 days between the two doses. Serial blood samples were taken and pharmacokinetic parameters calculated and statistically analyzed from mirtazapine plasma levels. The extent of absorption of mirtazapine, as measured by the area under the plasma level versus time curve, was found to be equivalent for the fasting and the fed state. Food intake was shown to have no influence on the elimination of mirtazapine, as measured by its elimination half-life. The rate of mirtazapine absorption, as measured by the peak level (Cmax), was not altered by food. The peak time (tmax), however, in subjects in the fed state showed an increase: the 90%-confidence interval for the median difference ranged from 0.25 to 1.25 h. This was the only effect of food found in this study. It is considered to be of no clinical consequence.

Purpose: To compare, in a clinical study of a special design, the pharmacokinetic profile of mirtazapine in 20 young healthy male volunteers on two treatment regimens with homothetic oral tablets at steady state: NOCTE (1 x 30 mg at 21.00 h) and BID (15 mg at 21.00 h and 15 mg at 09.00 h)., Methods: Pharmacokinetic parameters were calculated from mirtazapine plasma levels assayed by gas chromatography with nitrogen-sensitive detection. A special analysis of variance allowed interesting interactions to be distinguished., Results: The steady state was reached after 4 and 6 days for NOCTE and BID respectively; the difference was presumably due to intersubject variability. In accordance with pharmacokinetic theory, the peak-to-trough ratio at steady state was significantly lower (twofold) for BID than for NOCTE. Within BID, a small difference (approx. 10%) was found in the extent of absorption between evening and morning administration. Although statistically significant, this difference meets strict bioequivalence requirements. The regimens NOCTE and BID were found to be bioequivalent for the steady-state area-under-the-curve-curve and the peak time. Bioequivalence testing for the peak level was not meaningful due to the difference in dosing regimens. The observed elimination half-lives of 19.7 +/- 3.0 h and 20.8 +/- 2.7 h (n = 20) for NOCTE and BID, respectively are in agreement with previous results., Conclusions: Differences (if any) were found to meet strict bioequivalence requirements and were so small that they are of no clinical consequences.

Objective: To demonstrate that pharmacokinetic measurements were made at steady state. Subsequently, dose proportionality for desogestrel and ethinyl E2 kinetics were demonstrated., Design: Open-label, noncomparative study., Setting: Healthy volunteers in an academic research environment., Participants: Twenty white women who were 19 to 32 years old were solicited via an advertisement. Nineteen of the 20 women completed the study., Interventions: Study medication consisted of three cycles of a triphasic oral contraceptive containing desogestrel and ethinyl E2. Blood samples were taken at baseline and during cycle 3 between -48 and 24 hours on days 1, 7, 14, and 21, with additional sampling times on day 21 at 48, 60, and 72 hours., Main Outcome Measures: Serum concentrations of 3-keto-desogestrel and ethinyl E2., Results: Evaluation of the trough serum levels indicated that a steady state of 3-keto-desogestrel had been reached. Statistical analysis on the Cmax, area under the curve (AUC), and Css,min indicated dose proportionality for the administered desogestrel. Ethinyl E2 serum levels obtained at the same time points also reflected steady state levels and showed minimal variability. The statistical analysis on Cmax, AUC, Css,min, and Tmax indicated that the pharmacokinetics of ethinyl E2 on days 7, 14, and 21 were not statistically significantly different, indicating dose equivalency., Conclusions: Steady state of 3-keto-desogestrel is reached after each of the three phases and the pharmacokinetics are dose proportional. After reaching steady state, the pharmacokinetics of ethinyl E2 remain constant over time.

Pharmacokinetics of 3-keto-desogestrel and ethinylestradiol released from contraceptive vaginal rings (CVRs) with different release rates (75/15, 100/15 and 150/15 micrograms 3-keto-desogestrel/ethinylestradiol daily) were investigated in two studies in young healthy female volunteers. As reference, an oral preparation containing 150 micrograms desogestrel and 30 micrograms ethinylestradiol (MarvelonR tablets) was also administered to the volunteers. To assess the disposition parameters of 3-keto-desogestrel and ethinylestradiol, some of the volunteers were additionally given an i.v. preparation containing 150 micrograms 3-keto-desogestrel and 30 micrograms ethinylestradiol. Serum levels obtained with CVRs showed an initial increase during the first three days, followed by a plateau decreasing only slightly during the remainder of the treatment period. Mean plateau levels (+/- s.d.) of 3-keto-desogestrel were 2.3 +/- 0.9, 2.8 +/- 1.1 and 3.8 +/- 1.1 pmol/ml for CVR 75/15, 100/15 and 150/15, respectively. Mean plateau levels of ethinylestradiol were 184 +/- 75, 262 +/- 102 and 233 +/- 102 pmol/l, respectively. The in vivo release rates of 3-keto-desogestrel and ethinylestradiol from the CVRs were in good agreement with the in vitro release rates. For both steroids the bioavailability from the CVRs was approximately 1.2 times higher than that from the tablets. The 3-keto-desogestrel serum levels were found directly proportional to the release rates within the range studied (75-150 micrograms/day). For ethinylesteradiol the intra-individual variation in steady-state levels was too large to draw pertinent conclusions.

The present study was conducted to derive pediatric mianserin pharmacokinetic parameters, which were compared to those from healthy young adults, and to obtain preliminary information regarding the utility of mianserin for the management of hyperkinesis in children. The sample consisted of six prepubescent children with hyperkinetic behavior disorders who had not responded, or had developed tolerance to, stimulant medication. Mianserin pharmacokinetics were derived from plasma samples obtained over a 36- to 50-hour period following a single oral dose which ranged from 0.28 to 0.72 mg/kg. Children evidenced a significantly faster elimination half-life and a significantly smaller apparent kinetic volume of distribution than did adults, whereas maximum plasma concentration, time to maximum concentration, and apparent oral plasma clearance were similar. Ratings of behavioral deviance were obtained from teachers and parents during placebo and mianserin titration to a maximum dose of 40 mg/day. Although half the children showed some decrease in hyperactivity ratings, the small sample size and high variability of response preclude conclusions regarding the efficacy of mianserin for childhood hyperkinesis. Possible side effects in our sample included akathisia, excitability, insomnia, and migraine-like headache, as well as cardiovascular effects of tachycardia and two instances of minor electrocardiographic change. Our pharmacokinetic findings will be of import should mianserin prove useful for such childhood disorders as depression and/or enuresis.(ABSTRACT TRUNCATED AT 250 WORDS)

For bioequivalence testing of pharmaceutical formulations of the same drug entity, it is not sufficient to carry out an analysis of variance on the characteristic to be evaluated (e.g., area under the plasma level vs time curve, half-life of elimination, time to plasma-peak level, plasma peak level) and to establish 'classical' 95% confidence intervals for the difference or the ratio of the characteristic concerned. In the past 10 years, several approaches have been proposed as an aid in decision-making: Westlake's 95% intervals, Rodda and Davis' probabilities, Fluehler's posterior probability histograms and the evaluation of the residual variation coefficient. A survey of these approaches is given, together with a discussion of their merits, their differences and their similarities. It is recommended that the final evaluation should be supported by probability density plots, which facilitate easy understanding of the differences and similarities between the various approaches. A bioequivalence study with two types of oral tablets containing bepridil, a new anti-anginal drug, is used as an example. Computer programs are presented, which enable the user to easily apply the various approaches in order to meet requirements of regulatory agencies.

A pharmacokinetic study with mianserin . HCl was performed in six healthy male subjects. The subjects were treated on different occasions intravenously with a constant-rate infusion of 5 mg mianserin. HCl in 1 h, orally with a single dose of 60 mg as two tablets of 30 mg each and with 60 mg as an oral solution. The wash-out period between treatments was 1 month. Blood samples were taken at predetermined times over a period of 120 h following dosing. The mianserin concentration in the plasma samples was determined and the results were pharmacokinetically analyzed. The intravenous data could be adequately described by a 3-compartment model and the oral data by a 2-compartment model, both with first-order transfer and elimination rate constants. The mean plasma clearance of mianserin was found to be 19 +/- 2 l h-1 (mean +/- SEM), the kinetic volume of distribution 444 +/- 250 l, the steady-state volume of distribution 242 +/- 171 l and the elimination half-life 33 +/- 5 h. The absolute bioavailability in terms of extent of absorption was 22 +/- 3% for the solution and 20 +/- 3% for the tablets. The mean peak level for the solution was 79 +/- 11 ng X ml-1 and for the tablets 54 +/- 5 ng X ml-1; mean peak time for the solution was 1.1 +/- 0.2 h and for the tablets 1.4 +/- 0.2 h. The mean absorption half-life for the solution was 0.43 +/- 0.13 h and for the tablets 0.39 +/- 0.11 h.(ABSTRACT TRUNCATED AT 250 WORDS)

An assay method has been developed to determine the free base of Org 6001 (3 alpha-amino-5 alpha-androstan-2 beta-ol-17-one . HCl) in biological samples. The assay procedure consists of protein denaturation, ethyl acetate extraction, derivatization with tert-butyldimethylchlorosilane in dimethylformamide followed by n-hexane extraction and selected ion monitoring using trideuterated Org 6001 as an internal standard. For quantitation, the signals were monitored corresponding to the masses of the [M - 57]+ ions of 2-O-tert-butyldimethylsilyl, N-formyl derivatives of Org 6001 and the internal standard at m/z 390 and m/z 393, respectively. The assay method was applied to plasma samples from the human and rat, and to rat tissues including the target organ, the heart. The relationship between the Org 6001 plasma level and clinical effect in the human, the distribution of Org 6001 in rat tissues, and the correlation between the plasma level and the amount of Org 6001 in total heart tissue of the rat were determined.