A high performance normally closed solenoid-actuated cold valve.

An electromagnetically driven normally closed valve for liquid helium is presented, which is meant to regulate the input flow to a 1 K pot. An earlier design is modified to be normally closed (not actuated) and tuned for durability and reliability. A new feature is presented which prevents seat deformation at room temperature and provides comfort and durability for intensive use.

A nonlinear compartmental model of Sr metabolism. I. Non-steady-state kinetics and model building.

A model of Sr metabolism was developed by using plasma and urinary Sr kinetic data obtained in groups of postmenopausal women who received four different oral doses of Sr and collected during the Sr administration period (25 days) and for 28 days after cessation of treatment. A nonlinear compartmental formalism that is appropriate for study of non-steady-state kinetics and allows dissociation of variables pertaining to Sr metabolism (system 1) from those indirectly operating on it (system 2) was used. At each stage of model development, the dose-dependent model response was fitted to the four sets of data considered simultaneously (1 set per dose). A seven-compartment model with internal Sr distribution and intestinal, urinary, and bone metabolic pathways was selected. It includes two kinds of nonlinearities: those accounting for saturable intestinal and bone processes, which behave as intrinsic nonlinearities because they are directly dependent on Sr, and extrinsic nonlinearities (dependent on system 2), which suggest the cooperative involvement of plasma Sr changes in modulating some intestinal and bone mineral metabolic pathways. With the set of identified parameter values, the initial steady-state model predictions are relevant to known physiology, and some peculiarities of model behavior for long-term Sr administration were simulated.

A nonlinear compartmental model of Sr metabolism. II. Its physiological relevance for Ca metabolism.

We have studied the peculiarities of the nonlinear compartmental model for human Sr metabolism (Staub JF, Foos E, Courtin B, Jochemsen R, and Perault-Staub AM. Am J Physiol Regul Integr Comp Physiol 284: R819-R834, 2003), including its physiological reliability in the context of Sr-Ca similarity-dissimilarity. We found it to be relevant to Ca metabolism, except for discrimination against Sr relative to Ca at urinary and intestinal levels. The main findings are as follows: 1) the saturable part of intestinal absorption, shared by Sr and Ca, does not seem to be responsible for the discrimination of the transcellular pathway; 2) although there is little discrimination in bone, the physicochemical behaviors of Sr and Ca at the bone surface differ, at least quantitatively; and 3) Sr behaves as a "tracer" for Ca metabolic pathways and, under non-steady-state conditions, can also reveal self-regulatory processes. It is suggested that they depend on Ca2+ (cationic)-sensing receptors that are apparently more sensitive to Sr than to Ca. Acting on gastrointestinal and osteoblast lineage cells, these slow processes might contribute to adaptive, rather than homeostatic, regulation of Ca metabolism. Understanding these features could help clarify the pharmacological and therapeutic effects of oral Sr.

Complete bioavailability and lack of food-effect on pharmacokinetics of gliclazide 30 mg modified release in healthy volunteers.

A new modified release (MR) formulation containing 30 mg of gliclazide was developed to obtain a better predictable release of the active principle and to allow once-daily dosing regimen. An absolute bioavailability study was carried out to characterise the performance of the new formulation and the food-effect was also investigated in a separate study. Both studies were single dose, randomised, open label, two way cross over studies with a wash out period between doses. For the bioavailability study, each volunteer received 30 mg of gliclazide given either as a 1 h intravenous infusion or as a 30 mg MR tablet. For the food-effect study, the treatment was given either fasted or 10 min after the start of a standardised Melander breakfast. Blood samples were collected up to 72 h after administrations and plasma samples assayed for gliclazide concentrations using a reverse-phase HPLC method with UV detection. Mean absolute bioavailability of gliclazide was 97% and ranged between 79 and 110% showing complete absorption. A similar moderate to low variability was observed after IV and oral administration showing the MR formulation did not add to the overall variability which is solely due to the disposition parameters, in particular metabolism of gliclazide. No significant difference was observed in t(max), t(1/2z), C(max) and AUC of gliclazide after administration of the 30 mg MR tablet under fasted and fed conditions. In conclusion, after single oral administration of a 30 mg MR tablet, gliclazide was completely absorbed both under fasted and fed conditions. A consistent and optimal release of gliclazide from this formulation leads to a low to moderate overall variability of its pharmacokinetic parameters. Diamicron 30 mg MR can be given without regards to meals i.e. before, during or after breakfast.

Dose-effect relationship for several coagulation markers during administration of the direct thrombin inhibitor S 18326 in healthy subjects.

AIMS: We conducted a phase I placebo-controlled trial with two i.v. doses (0.5 mg h-1 and 3 mg h-1) of S 18326, a selective thrombin inhibitor that interacts with the catalytic site of thrombin, with the aim to study the relationships between increasing plasma levels of S 18326 and changes in coagulation tests and thrombin generation markers. METHODS: Thirty-six healthy male volunteers were divided into three groups. In each group, 10 volunteers were randomly assigned to receive S 18326 and two to receive a placebo. Following a bolus of 4.5 mg, doses were 0.5 mg h-1 in the first group and 3 mg h-1 in the two other groups, administered as an i.v. infusion for 24 h. Blood was drawn repeatedly up to 36 h after the bolus, and tested for the activated clotting time (ACT) and activated partial thromboplastin time (APTT). The APTT reagent was chosen among five commercial reagents to yield a linear increase in the clotting time among possible therapeutic S 18326 concentrations in vitro. To accurately measure the thrombin-inhibiting effects of low doses of S 18326 (< 0.5 microm), we developed a specific chromogenic assay. We also measured F1 + 2 prothrombin fragment levels to assess the effect of S 18326 on thrombin generation in vivo. RESULTS: A two-compartment pharmacokinetic model was fitted to the S 18326 plasma concentration vs time data by using population pharmacokinetic methods. Results of the pharmacodynamic-pharmacokinetic relationships showed that both the ACT and APTT methods yielded a linear increase according to the S 18326 concentration measured using a highly sensitive analytical method. At the end of infusion, ACT was prolonged 1.20 and 1.95-fold in the 0.5 mg h-1 and the 3 mg h-1 groups, respectively, and APTT was prolonged 1.27 and 2.75-fold. Thrombin inhibition plateaued above 0.5 microm of S 18326 according to an Emax model, confirming that the test was highly sensitive. F1 + 2 levels fell significantly after the 24 h S 18326 infusion (0.83 nm to 0.6 nm and 0.80 nm to 0.44 nm in the 0.5 mg h-1 and the 3 mg h-1 groups, respectively), but remained stable after the placebo infusion. CONCLUSIONS: Our results support specific monitoring of the thrombin inhibitor S 18326 with ACT and APTT to establish the safety range of the drug in further studies. Moreover, the fall in F1 + 2 prothrombin fragments suggests that S 18326 effectively reduces the retroactivation of factors V and VIII by thrombin.

Anisotropy of growth kinetics of 3He crystals below 1 mK.

The growth anisotropy of different facets has been measured in 3He crystals at 0.55 mK using a low-temperature Fabry-Pérot interferometer and high-resolution pressure measurements. The observed linear dependence of the growth velocity on the driving force shows that facets grow due to the presence of dislocations. The values of the obtained step energies suggest that 3He has stronger coupling of the liquid-solid interface to the lattice than has been expected. The dependence of the step energy versus the step height is consistent with a quartic power law pointing out that the step-step interactions are of elastic origin.

Faceting on He crystals.

It has been predicted by Landau that, ideally at low temperatures, crystals should show many different types of facets, i.e., flat smooth faces on their surface, but this so-called "devil's staircase" phenomenon has been difficult to observe experimentally. In this paper we describe our recent experiments, in which altogether 11 different types of facets have been identified on growing (3)He crystals at the temperature of 0.55 mK by using a unique low-temperature Fabry-Pérot interferometer. Previously only 3 types of facets had been seen in this system. We have also measured the growth velocities of different facets, and our interpretation of the obtained results yields the conclusion that (3)He has much stronger coupling of the liquid-solid interface to the crystal lattice than has been expected. After an introduction we present a short theoretical background about the equilibrium crystal shape and the roughening transitions, which is followed by the description of our experimental results and discussion.

Population pharmacokinetic-pharmacodynamic modelling of S 15535, a 5-HT(1A) receptor agonist, using a behavioural model in rats.

The pharmacokinetic-pharmacodynamic relationship of S 15535 (1-(benzodioxan-5-yl) 4-(indan-2-yl)piperazine) and its active 5-hydroxy metabolite S 32784 (1-(benzodioxan-5-yl) 4-(5-hydroxyindan-2-yl)piperazine), and buspirone as a reference, were studied in male Wistar rats using a behavioural model of anxiety by determining the reduction in the number of fear-induced ultrasonic vocalisations. S 15535 and buspirone were administered p.o. and i.v. S 32784, present in man but not in rat, was administered i.v. The pharmacokinetics and pharmacokinetic-pharmacodynamic relationships were described using non-linear mixed effects modelling. The no-drug effect was constant and all compounds were active in the model, reducing ultrasonic vocalisations immediately after administration. The sigmoid E(max) model was used to describe the pharmacokinetic-pharmacodynamic relationships, with E(max) values of a 90% decrease in baseline ultrasonic vocalisations. Corrected for plasma protein binding, all compounds showed similar potency. The study shows that ultrasonic vocalisations can be considered a suitable endpoint for the anxiolytic effect when used in conjunction with non-linear mixed effects modelling to overcome the limited sampling and effect measurements.

Observation of higher order facets on 3He crystals.

Faceting has been observed on 3He crystals investigated with a low-temperature Fabry-Pérot interferometer. Nine types of facets were clearly identified during growth of a bcc- 3He single crystal at a temperature of 0.55 mK, while previously only three types of facets have been seen. Because of the weak coupling between the liquid-solid interface and the solid lattice in 3He the facets are apparently too small to be observed in equilibrium. The number of facets observed in our experimental conditions is consistent with the theory of dynamic roughening.

Pharmacokinetic-pharmacodynamic modelling in the early development phase of anti-psychotics: a comparison of the effects of clozapine, S 16924 and S 18327 in the EEG model in rats.

1. The use of pharmacokinetic/pharmacodynamic (PK/PD) analysis in early compound development was investigated in the rat for two developmental anti-psychotic compounds with clozapine as a positive control. 2. Three plasma samples were collected from each of eight animals according to a pre-defined sampling matrix allowing a total of 12 time points for PK analysis. Quantitative electroencephalography (QEEG), particularly the theta and beta frequencies, was used as a measurement of pharmacological effect. 3. PK/KD modelling of the sparse PK data available relative to a rich set of PD data was achieved using a population approach in NONMEM (IV). Individual PK parameter estimates were incorporated into a PK/PD model. 4. Qualitative EEG changes in rat and human were similar for clozapine, but different for the two developmental compounds, suggesting that changes in these PD parameters may not be specifically related to the anti-psychotic activity. 5. Although no definitive data are available concerning the signal specificity of EEG frequency bands with respect to dopaminergic or serotonergic receptor activity, qualitative and quantitative differences seen in EEG parameters are likely to result from the multiple receptor occupancy for these compounds. 6. The results confirm the value of population PK/PD modelling in conjunction with sparse sampling to enable determination of concentration effect relationships in the pre-clinical development programme of CNS-active drugs.

Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling.

A strategy is presented to predict interindividual variation in drug plasma levels in vivo by the use of physiologically based pharmacokinetic modeling and human in vitro metabolic parameters, obtained through the combined use of microsomes containing single cytochrome P450 enzymes and a human liver microsome bank. The strategy, applied to the pharmaceutical compound (N-[2-(7-methoxy-1-naphtyl)-ethyl]acetamide), consists of the following steps: (1) estimation of enzyme kinetic parameters K(m) and V(max) for the key cytochrome P450 enzymes using microsomes containing individual P450 enzymes; (2) scaling-up of the V(max) values for each individual cytochrome P450 involved using the ratio between marker substrate activities obtained from the same microsomes containing single P450 enzymes and a human liver microsome bank; (3) incorporation into a physiologically based pharmacokinetic model. For validation, predicted blood plasma levels and pharmacokinetic parameters were compared to those found in human volunteers: both the absolute plasma levels as well as the range in plasma levels were well predicted. Therefore, the presented strategy appears to be promising with respect to the integration of interindividual differences in metabolism and prediction of the possible impact on plasma and tissue concentrations of drugs in humans.

Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat.

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.

Melting process and interface instability of highly magnetized solid 3He: role of the magnetization gradient

We elucidate the melting process of highly magnetized solid 3He by observing the magnetization profile and the liquid-solid interface simultaneously. Clear enhancements of magnetization and magnetization gradients at the interface of both the solid and the liquid were observed during melting. These measurements provide a mesoscopic confirmation of the melting scenario of Castaing and Nozieres, and explain the long delay before the instability sets in: The magnetization gradient in the liquid leads to an initial suppression of the melting instability, in accordance with our extension of the stability analysis of Puech et al. This resolves the discrepancy between theory and experiment.

Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study.

AIMS: The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers. METHODS: This was a double-blind, randomized, placebo-controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection. RESULTS: PEP activity in plasma was dose-dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5-2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half-life (t(1/2)) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose. CONCLUSIONS: S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once-daily dosing without any serious adverse events.

Pharmacokinetics of sustained and immediate release formulations of indapamide after single and repeated oral administration in healthy volunteers.

The pharmacokinetics of a 2.5 mg immediate release (IR) formulation of indapamide was compared to a 1.5 mg sustained release (SR) formulation of indapamide after single and repeated oral administration dose using double blind randomised cross-over studies. In the first study, 12 subjects received a single dose of each treatment: IR fasted, SR fasted or with food. In the second study one tablet of either formulation was administered daily for one week at breakfast. In each study, blood samples were collected pre dose (Cmin) and up to 120 h after the last dose. Urine was collected over the dosing interval (24 h). Following a single oral administration the SR formulation had a lower dose-normalised Cmax compared to the IR formulation (17.6 +/- 6.3 vs. 39.3 +/- 11.0 ng x mL(-1), respectively), a much longer t(max) (12.3 +/- 0.4 vs. 0.8 +/- 0.3 h) and a greater t75 (15.3 +/- 6.1 vs. 1.8 +/- 1.4 h) but there were no differences in dose-normalised AUC (559 +/- 125 and 564 +/- 146 ng x h x mL(-1)) nor in t(1/2z) values (14.8 +/- 2.8 vs. 18.4 +/- 13.4 h). The SR formulation clearly demonstrated sustained release characteristics as compared to the IR formulation. Food co-administration had no effect on dose-normalised AUC for the SR formulation. After repeated administration, steady-state was achieved by day 5. The absorption rate of the SR formulation was lower and the 24 h peak-to-trough fluctuation was 4-fold lower compared to the IR formulation. After dose correction there wasno change in AUC, (726 +/- 207 and 690 +/- 183 ng x mL(-1) x h for SR and IR, respectively). The elimination parameters (t(1,2z), Ae(tau), and CLr) remained unchanged. The SR formulation showed sustained release of indapamide with a reduction in peak concentration, while steady-state level was not affected by formulations. The two formulations have the same bioavailability.

Use of nonlinear mixed effect modeling for the meta-analysis of preclinical pharmacokinetic data: application to S 20342 in the rat.

The standard two-stage analysis of separate preclinical pharmacokinetic (PK) and toxicokinetic (TK) studies may lead to good information on the bioavailability in the rat at a low (pharmacologic) dose but only an idea on the dose/exposure relationship, on gender, and on time effect. In view of these drawbacks, we decided therefore to explore the usefulness of the implementation of a meta-analysis in preclinical studies in a given species (the rat in this case) taking as an example S 20342, an investigational new drug with potential antipsychotic properties. A nonlinear mixed-effect PK model was built from all intravenous (IV) and oral (PO) data collected until the completion of the 4-week toxicity study. The database included data from 201 Wistar rats (161 males and 40 females). Forty animals received the drug IV and 161 PO. The treatment duration ranged from 1 day to 4 weeks. IV doses were 3, 5, and 20 mg/kg, and 11 different oral doses were tested in the range of 5 to 200 mg/kg. Three different salts were administered PO: hydrochloride, sulfate, and mesylate. The modeling was performed with NONMEM IV. The best pharmacokinetic model was a two-compartment model with simultaneous first-order and zero-order absorption. The combination of these two input functions allowed the model to fit the peak plasma concentrations observed in the first hour (first order), especially after oral administration of low doses, and to take into account the prolonged absorption phase when the dose increased (zero order). A significant gender effect was found on CL. In addition, significant positive correlations were found between weight and CL, weight and Vc, and dose and the dose fraction after a zero-order absorption. No covariate significantly influenced the other parameters. In conclusion, the meta-analysis of preclinical data allowed for an objective assessment of statistically significant effects throughout the model-building process, leading to a better knowledge (and thus a better understanding) of preclinical PK in the rat. Moreover, the model obtained could be used to interpret further preclinical specific studies involving a sparse sampling design (e.g., further TK studies and PK/PD studies). Although this meta-analysis is more complicated than the noncompartmental approach and requires a case-by-case effort, it could be very useful to integrate this approach in the preclinical development process.

Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers.

OBJECTIVE: Ivabradine (S-16257) is a new bradycardic agent with a direct effect on the sinus node. Its N-dealkylated metabolite, S-18982, has shown a bradycardic activity in animals. The aim of this trial was to study the correlation between drug bradycardic activity and plasma levels of the parent compound and its metabolite in healthy volunteers. METHODS: Eighteen healthy volunteers participated in three successive study periods: an oral double-blind period with two parallel groups of doses (10 or 20 mg, single and repeated); a 10 mg intravenous bolus open period; and a final control period. The effects of ivabradine on heart rate were studied at rest and during bicycle exercise tests (at 85% of maximum workload) during 24-hour postdosing, and ivabradine and S-18982 plasma levels were determined simultaneously. RESULTS: The maximal reductions of exercise heart rate were 11% +/- 4% (10 mg) and 18% +/- 6% (20 mg) after single oral doses (p < 0.05) and 18% +/- 4% (10 mg) and 27% +/- 6% (20 mg) after repeated doses (p < 0.01). Maximum heart rate reduction after the intravenous bolus was 19% +/- 4%. After oral administrations an indirect relationship between the bradycardic effect and the plasma concentrations of the two compounds was found. A pharmacokinetic/pharmacodynamic population analysis done with the NONMEM computer program showed that S-18982 contributes in part to the overall activity of ivabradine: modeling suggested that the metabolite is responsible for the initial bradycardic effect, whereas the parent compound is responsible for the duration of action. CONCLUSION: This study shows that ivabradine exerts a dose-dependent bradycardic effect and that its N-dealkylated metabolite contributes to this bradycardic effect.

Application of population pharmacokinetics to the phase II development of an anti-Alzheimer's disease compound, S12024.

Steady-state concentrations of S12024, a novel compound for treatment of Alzheimer's disease, were studied to determine the pharmacokinetic parameters of S12024 in Phase IIa patients and to assess the effect of patient characteristics on those pharmacokinetics. A prospective sparse sampling strategy was used to obtain oral repeated data (n = 285) from 89 patients, which were analyzed using a one-compartment model and the NONMEM computer program. The model suggested that apparent clearance of S12024 was influenced by the study and by patient age. In the Spanish study, apparent clearance was increased by 68% and 26% for doses of 100 mg and 300 mg, respectively, and patient age decreased oral clearance by approximately 10% per decade in the patient age range (50 to 90 years). Data from only a few patients in the Spanish study were probably responsible for the observed study influence on apparent clearance of S12024, and no measured covariates could explain this effect. The model provided an excellent characterization of the observed data and it predicted correctly the plasma concentrations from an earlier Phase I trial and a subsequent Phase IIb study. The present model, built from Phase IIa data, provides a basis for examining the influence of patient covariates and the magnitude of their effects on the pharmacokinetics of S12024. The study effect is probably an artefact that will disappear by further expanding of the population model in the future.