Investigation of ISIS and Brookhaven National Laboratory ion source electrodes after extended operation.

Linac4 accelerator of Centre Européen de Recherches Nucléaires is under construction and a RF-driven H(-) ion source is being developed. The beam current requirement for Linac4 is very challenging: 80 mA must be provided. Cesiated plasma discharge ion sources such as Penning or magnetron sources are also potential candidates. Accelerator ion sources must achieve typical reliability figures of 95% and above. Investigating and understanding the underlying mechanisms involved with source failure or ageing is critical when selecting the ion source technology. Plasma discharge driven surface ion sources rely on molybdenum cathodes. Deformation of the cathode surfaces is visible after extended operation periods. A metallurgical investigation of an ISIS ion source is presented. The origin of the deformation is twofold: Molybdenum sputtering by cesium ions digs few tenths of mm cavities while a growth of molybdenum is observed in the immediate vicinity. The molybdenum growth under hydrogen atmosphere is hard and loosely bound to the bulk. It is, therefore, likely to peel off and be transported within the plasma volume. The observation of the cathode, anode, and extraction electrodes of the magnetron source operated at BNL for two years are presented. A beam simulation of H(-), electrons, and Cs(-) ions was performed with the IBSimu code package to qualitatively explain the observations. This paper describes the operation conditions of the ion sources and discusses the metallurgical analysis and beam simulation results.

A subKelvin scanning probe microscope for the electronic spectroscopy of an individual nano-device.

We present a combined scanning force and tunneling microscope working in a dilution refrigerator that is optimized for the study of individual electronic nano-devices. This apparatus is equipped with commercial piezo-electric positioners enabling the displacement of a sample below the probe over several hundred microns at very low temperature, without excessive heating. Atomic force microscopy based on a tuning fork resonator probe is used for cryogenic precise alignment of the tip with an individual device. We demonstrate the local tunneling spectroscopy of a hybrid Josephson junction as a function of its current bias.

Induction of fertile oestrus in the bitch using Deslorelin, a GnRH agonist.

Oestrus induction in various canine breeds was attempted in 32 bitches. A group of 8 bitches were treated 80-160 d following their previous oestrus (G1) whereas a second group of 24 bitches (G2) were implanted 200-590 d following their previous oestrus. The treatment for each bitch consisted in one Deslorelin implant (Suprelorin® 4,7 mg, Virbac, France), inserted subcutaneously in the post-umbilical region. Ovulation, pregnancy rate and litter size were recorded. All bitches came in heat 4.3 ± 1.4 d after implantation (2-7 d). Ovulation was reported in 62.5% in G1 and 87.5% in G2. One bitch refused mating and since no AI was performed, she was not considered for further analysis. Pregnancy was obtained in 25% in G1 versus 78.3% in G2. Mean litter size was 6.7 ± 3.5 puppies (1-14). Luteal failure was suspected in 3 bitches, two that remained non-pregnant and one which aborted 58 d post-ovulation since the owner refused progesterone supplementation. Deslorelin implants can therefore be considered as a valuable alternative to induce fertile oestrus in bitches in anoestrus. Follow-up of the luteal phase is recommended, since some bitches might encounter luteal failure.

Absolute bioavailability of carbamazepine after oral administration of a 2% syrup.

Two healthy male volunteers received 10 mg carbamazepine (CBZ) as a 2-h constant-rate intravenous (i.v.) infusion and 100 mg 15N-labeled CBZ as a 2% oral suspension, concomitantly. The two compounds have identical pharmacokinetics. Their respective concentrations in plasma were determined by gas chromatography-mass spectrometry (GC-MS) for 168 h. The comparison of the areas under the plasma curves (AUC) obtained by the two routes of administration, showed the systemic availability of CBZ given as an oral suspension to be equal to its availability when given intravenously. A two-compartment model was estimated: The apparent volume of distribution of CBZ at the steady-state (Vss) was approximately 1 L/kg.

Bioequivalence of carbamazepine chewable and conventional tablets: single-dose and steady-state studies.

Single-dose and steady-state studies were carried out on separate occasions to examine the bioequivalence of the newly formulated carbamazepine chewable tablet. In the single-dose study, the plasma levels resulting from 2 X 200-mg conventional tablets (CT), 4 X 100-mg chewable tablets swallowed whole (SW), and 4 X 100-mg chewable tablets chewed before swallowing (CHEW) were compared. A randomized 3 X 3 Latin-square design balanced for residual effects, with a 3-week washout period, was used (n = 6). Plasma samples were analyzed by a specific GC method for carbamazepine. The following parameters were used for evaluation: AUC, Cmax, tmax, and t1/2. None of the parameters were significantly different except Cmax and t1/2 values for CHEW and CT. The Cmax was 25% higher and t1/2 was 11% shorter for CHEW than CT. The impact of differences in the peak plasma levels at steady state were examined by pharmacokinetic projection (400 mg b.i.d.) based on the single-dose data and with simulated induction equal to a 50% reduction in t1/2. The projected steady-state CT and CHEW plasma concentrations were similar, with a difference of only 4%. The results demonstrate the bioequivalence of the dosage forms with respect to the extent of absorption, and similar steady-state concentrations of carbamazepine in plasma can be expected. To test the conclusion from the projected study, a separate bioequivalence study to compare CHEW relative to CT was performed at steady state in normal volunteers (200 mg b.i.d.).(ABSTRACT TRUNCATED AT 250 WORDS)

Glycerol trinitrate (nitroglycerin) plasma concentrations achieved after application of transdermal therapeutic systems to healthy volunteers.

Glycerol trinitrate (nitroglycerin, in the following briefly called GTN) plasma concentrations achieved upon application of a commercial scale produced transdermal therapeutic system containing GTN (TTS-GTN, Nitroderm-TTS) were compared to those induced by 2 TTS-GTN prototypes previously used for clinical trials. Each system was applied to the chest, lateral aspect, of 14 healthy volunteers for 24 h, in a 3-period change-over study. GTN in plasma was determined by gas chromatography-mass spectrometry. The 3 systems released the drug continuously over 24 h. The mean plasma concentrations for all subjects and all sampling times (nmol/l) +/- SE were 0.92 +/- 0.18, 0.80 +/- 0.12 and 0.97 +/- 0.18 for the commercial scale TTS and the 2 other systems, respectively. No significant differences were demonstrated. The mean delivery rate of GTN calculated from the initial and residual contents of the TTS was 6.8 micrograms/min as a mean for the 3 systems. In another study, three different application sites were compared (chest, upper arm and pelvis). The results did not demonstrate significantly different GTN plasma levels. A comparison with published data after intravenous infusion showed a good availability of GTN administered transdermally by means of TTS. Its magnitude seems comparable to that of the intravenous route.

Osmotically controlled-delivery of metoprolol in man: in vivo performance of Oros systems with different durations of drug release.

In vivo absorption from 19/190 and 19/285 metoprolol Oros drug delivery systems has been assessed by measuring plasma drug concentrations after single administration of the systems to six healthy volunteers. The initial in vitro release rate for both Oros preparations was 19 mg/h but they contained 190 or 285 mg of metoprolol fumarate. The plasma concentration-time profiles for both Oros dosage forms were consistent with an extended duration of release and absorption from the gastrointestinal tract. Analysis of the plasma level data indicated that the rate and duration of in vivo absorption closely mirrored the in vitro release behaviour of the 19/190 and 19/285 systems, but the in vivo profiles showed a 1-2 h initial delay. The administration of the 19/190 system on two occasions to the same six volunteers indicated that in vivo release of drug from this Oros preparation was reproducible.

Quantitative determination of nitroglycerol in human plasma by gas chromatography negative ion mass spectrometry using 15N labelled nitroglycerol as internal standard.

Negative ionization resulted in the simplification of a previously published method. The new method permits the determination of 0.25 nmol l-1 nitroglycerol in plasma with a coefficient of variation of 9.1%.

Studies of the bioavailability of nitroglycerin from a transdermal therapeutic system (Nitroderm TTS).

In 6 healthy volunteers, intravenous infusions of nitroglycerin 4.8 and 10.6 micrograms/min yielded mean steady-state plasma concentrations of 0.5 +/- 0.02 and 0.82 +/- 0.04 ng/ml as determined by a gas chromatographic/mass spectrometric method. The plasma concentrations reached in the same subjects 17 h after application of Nitroderm TTS 5 and 10 with in vivo release rates of 3.7 and 5.7 micrograms/min were 0.28 +/- 0.01 and 0.37 +/- 0.01 ng/ml, respectively. Thus, 75% of the quantity of nitroglycerin released by the systems passed into the circulation. The inter-individual and intra-individual variations in plasma concentrations were similar for both modes of administration. The nitroglycerin-induced morphological changes in the fingerpulse wave were clearly dose-dependent, but it seems that this pharmacodynamic parameter is determined less by the plasma concentration than by the nitroglycerin content of the vascular wall.

[Comparative elimination of pirprofen from the plasma and synovial fluid of the knee. 26 cases]. / Elimination comparée du pirprofène à partir du plasma et du liquide synovial du genou. 26 observations.

Twenty-six patients with various inflammatory diseases of the knee were treated with a 400 mg dose of pirprofen orally twice a day for 2 days. On the third day, samples of blood and synovial fluid were taken 3 h and 10 h approximately after a fifth 400 mg dose of the drug. Pirprofen concentrations, as determined by gas-liquid chromatography, were higher in plasma than in synovial fluid during the 2-5 h period post-dosing. They decreased with an elimination half-life of 6 h in plasma as against 41 hours in synovial fluid. This study demonstrates that pirprofen diffuses into the synovial fluid where it remains significantly longer than in plasma.

An incremental method for the study of the absorption of drugs whose kinetics are described by a two-compartment model: estimation of the microscopic rate constants.

A method is proposed for estimating the overall absorption kinetics of drugs (expressed as percent of total amount absorbed versus time) from plasma data. It is applicable to the study of drugs whose kinetics can be described by linear one- or two-compartment models. Use is made of an iterative process based on the differential equations of the model and on linear interpolation of plasma data. The method does not require that the overall absorption kinetics should be apparent first-order and/or that the model parameters should be estimated from a previous experiment. It was tested for the influence of data scatter: added noise (CV = 10%) resulted in a variability of percent absorbed versus time of the same order of magnitude. During the calculations, the microscopic rate constants are estimated and optimalized. Data scatter resulted in wide variations in the estimates of the two-compartment model parameters. However, when a sufficiently large number of plasma concentration-time curves were studied, an average model could be determined with a reasonable precision. Model kinetics calculated from the related parameter estimates were in agreement with the theory. The method permits the exploitation of the various plasma concentration-time curves which are available after the development of an orally administered drug.

Absorption kinetics and model characteristics of orally administered pirprofen.

Pirprofen kinetics can be described by a linear two-compartment model. Absorption kinetics and model parameters were determined by the incremental method from 48 pirprofen plasma concentration-time profiles obtained after administration of single oral pirprofen doses. Statistical comparison of the results gave information on the influence of formulation, dose, and food on pirprofen absorption. The rate of absorption decreased significantly when pirprofen was administered as a capsule in comparison with a solution. The dose (200 mg compared with 100 mg) had no marked influence on the absorption rate. Food delayed absorption. Pirprofen model parameters, estimated as the median values of the results obtained from the 48 sets of data, permitted the plasma kinetics of the drug after single and repeated doses to be predicted.

Diffusion of oxyphenbutazone into synovial fluid, synovial tissue, joint cartilage and cerebrospinal fluid.

The diffusion of oxyphenbutazone into synovial and cerebrospinal fluids and synovium and joint cartilage was investigated in 25 patients receiving short-term treatment. In the synovial fluid, the mean oxyphenbutazone concentration, was 57.1 +/- 13.4% of the plasma level, due to its excellent diffusion into the joint cavity. In synovial tissue, the oxyphenbutazone level was higher in patients with severe inflammation than in those with no or little inflammation. Penetration into joint cartilage is less than into synovial tissue. In cerebrospinal fluid the concentration was close to the level of free plasma oxyphenbutazone. The findings show increased diffusion of oxyphenbutazone towards its site of action in inflammation.

Comparative pharmacokinetic profiles of metoprolol and chlorthalidone administered alone or in combination to healthy volunteers.

A potential pharmacokinetic interaction between the beta-blocking drug, metoprolol, and the diuretic, chlorthalidone, has been investigated in three single or multiple dose studies in healthy volunteers. The pharmacokinetic profile of metoprolol 100 mg was not affected by pretreatment with or co-administration of chlorthalidone 25 mg twice daily. Similarly, the pre-dosing steady-state level of chlorthalidone during chronic treatment and its blood level profile after a single 25 mg dose were not affected by metoprolol. The bioavailabilities of the 2 drugs administered in combination were identical to those observed when each drug was administered alone. These studies demonstrate that there is no pharmacokinetic interaction between metoprolol and chlorthalidone when doses of 100 and 25 mg, respectively, are co-administered twice daily.

Gas chromatographic mass spectrometric determination of 1,2,3-propanetrioltrinitrate (nitroglycerin) in human plasma using the nitrogen-15 labelled compound as internal standard.

A method for the quantitative determinatio of 1,2,3-propanetrioltrinitrate (nitroglycerin) in human plasma by gas chromatography mass spectrometry has been developed. After addition of 1,2,3 and methyl acetate (90 : 10). The extracts are purified by partition between, first, the extraction solvent and a mixture of acetonitrile and water (60 : 40) and, secondly, the resultant aqueous phase and benzene. THe solvent is evaporated to a small volume before injection. The fragment ions at m/z 46 and 47 are monitored for the measurement of the [NO2]+ and [15NO2]+ ions using electron impact ionization. The mean recovery (%) +/- SD in blind plasma samples spiked with amounts in the concentration range 0.35-3.52 nmol 1(-1), was 97.4 +/- 9.0 (n = 58). Within a day, recovery experiments gave rise to coefficients of variation of 9.6, 6.4 and 2.7% at the levels 0.44, 0.88 and 11 nmol 1(-1), respectively. Concentrations in plasma down to about 0.2 nmol 1(-1) (50 pg ml-1) could be estimated. Percent recovery of duplicate determinations in the range 0.5-1.96 nmol 1(-1) +/- SD was 99.4 +/- 6.0 (n = 80).

Pharmacokinetics of cefroxadin (CGP 9000) in man.

The pharmacokinetics of cefroxadin have been studied after the administration of single oral and intravenous doses to healthy volunteers. Cefroxadin was assayed by HPLC. The kinetics in plasma following i.v. administration were described by using a three-compartment model. An additional disposition phase was observed following oral administration that could not be detected after the low i.v. dose. The terminal half-life was 1.03 h. The apparent volume of distribution at the steady state was consistent with a diffusion of the antibiotic in all extracellular fluids. The AUC after oral administration was linearly related to the dose. The urinary excretion amounted to 95% of the dose with virtually complete absorption of orally administered drug.

Human pharmacological studies of a new transdermal system containing nitroglycerin.

A new transdermal therapeutic system (TTS) for the administration of nitroglycerin (NTG) was tested in human pharmacological studies in 26 healthy volunteers. Plasma concentrations and haemodynamic responses were determined after the application of the system in different dosages. The concentrations of NTG reached in the plasma were uniform and dose-related, i.e. dependent on the drug-release area, and showed only minor inter-individual variation. They remained almost constant as long as the system was in contact with the skin. Renewal of the system caused no appreciable change in the plasma concentration. The haemodynamic effects, like those of all nitrates, were not clearly related to the dose administered, and were not always dependent on the plasma concentration. Upon repeated application, NTG-TTS was well tolerated locally and systemically and led to no alteration in blood chemistry or haematological parameters. The typical nitrate headaches disappeared after a few days. The presence of the system on the skin caused no discomfort or inconvenience.