Origin of chaos near critical points of quantum flow.

The general theory of motion in the vicinity of a moving quantum nodal point (vortex) is studied in the framework of the de Broglie-Bohm trajectory method of quantum mechanics. Using an adiabatic approximation, we find that near any nodal point of an arbitrary wave function psi there is an unstable point (called the X point) in a frame of reference moving with the nodal point. The local phase portrait forms always a characteristic pattern called the "nodal-point- X -point complex." We find general formulas for this complex as well as necessary and sufficient conditions of validity of the adiabatic approximation. We demonstrate that chaos emerges from the consecutive scattering events of the orbits with nodal-point- X -point complexes. The scattering events are of two types (called type I and type II). A theoretical model is constructed yielding the local value of the Lyapunov characteristic numbers in scattering events of both types. The local Lyapunov characteristic number scales as an inverse power of the speed of the nodal point in the rest frame, implying that it scales proportionally to the size of the nodal-point- X -point complex. It is also an inverse power of the distance of a trajectory from the X point's stable manifold far from the complex. This distance plays the role of an effective "impact parameter." The results of detailed numerical experiments with different wave functions, possessing one, two, or three moving nodal points, are reported. Examples are given of regular and chaotic trajectories, and the statistics of the Lyapunov characteristic numbers of the orbits are found and compared to the number of encounter events of each orbit with the nodal-point- X -point complexes. The numerical results are in agreement with the theory, and various phenomena appearing at first as counterintuitive find a straightforward explanation.

The d-enantiomer form of indobufen totally accounts for the anti-cyclooxygenase and antiplatelet activity ex vivo and for the increase in bleeding time by indobufen in man.

Indobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean +/- S.D., 58.7 +/- 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 +/- 3% for both treatments). At 12 h inhibition was 87 +/- 6% for d-indobufen and 88 +/- 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of grepafloxacin after oral administration of single and repeat doses in healthy young males.

The pharmacokinetics of grepafloxacin in healthy male subjects following single oral administration of doses ranging from 200 to 1200 mg, and following repeated oral administration of 400 and 800 mg doses are reported. Plasma levels of grepafloxacin reached a peak within 2 hours (on average) following drug administration and then declined bi-exponentially with concentrations being detectable (> 5 micrograms/L) in the plasma for at least up to 72 hours postdose. The high values for the apparent volume of distribution (5 to 8 L/kg) suggested extensive distribution of grepafloxacin in the tissues. Only a small percentage of the administered dose (ranging from 6% to 9.5%) was recovered in the urine as unchanged grepafloxacin, suggesting that metabolism, rather than urinary excretion, is the major elimination route. The half-life of grepafloxacin was about 12 hours after single doses and about 15 hours after repeat doses. The trough levels increased significantly over the first 3 days of repeat administration; thereafter, the changes were small, with steady-state being reached by the fifth day. The area under the concentration-time curve (AUC24 h) values observed on days 7 and 14 of repeat administration, at each dose level, were similar, suggesting that steady-state is maintained. The area values increased more than proportionally after administration of increasing single and repeat doses, suggesting nonlinear kinetics. The elimination half-life and renal clearance did not change with increasing doses. Saturation in the metabolism of grepafloxacin and possibly in the distribution into a peripheral compartment, as suggested by a decrease in the total plasma clearance and in the apparent volume of distribution, could be the origin of the nonlinear kinetics. However, this deviation from linearity is unlikely to be of clinical significance, since it was very small over the recommended range of therapeutic doses (400 to 600 mg once daily). Compared with other quinolones, grepafloxacin showed the longest half-life and the highest apparent volume of distribution. These features, together with the excellent bactericidal activity of grepafloxacin, support the recommended dosage regimen of grepafloxacin for the treatment of respiratory tract infections and sexually transmitted diseases.

Effect of age and gender on the pharmacokinetics of grepafloxacin.

The effects of age and gender on the pharmacokinetics of the oral fluoroquinolone grepafloxacin were examined in 48 healthy middle-aged and elderly individuals, of whom half were male and half were female. Participants were stratified into 4 groups (each with n = 12), aged 40 to 49 years, 50 to 59 years, 60 to 69 years, and > 70 years. All received oral grepafloxacin 600 mg once daily for 7 days, and pharmacokinetic parameters were measured on days 1 and 7. Mean plasma grepafloxacin concentrations were consistently higher in females than in males. Peak concentrations, area under the concentration-time curve, apparent volume of distribution and apparent total clearance (but not renal clearance) differed significantly in females and males. There were no significant gender differences in the elimination half-life values. Further analysis of the data suggests that the gender-related pharmacokinetic differences were primarily due to differences in bodyweight, in particular to differences in lean body mass. The only parameters that changed significantly with age were renal clearance and the proportion of the dose excreted unchanged in the urine, but no clear trend was observed, and there was no correlation with creatinine clearance. We conclude that age and gender have no clinically significant effect on the pharmacokinetics of grepafloxacin. Dose adjustment on the basis of these factors does not therefore seem necessary.

Effect of food and gastric pH on the bioavailability of grepafloxacin.

Two open crossover studies were conducted to investigate the effects of food or concomitant treatment with the histamine H2-receptor antagonist famotidine on the pharmacokinetics of the new fluoroquinolone grepafloxacin. Each study involved 16 healthy male volunteers. In the first study, participants received grepafloxacin 600 mg, either after fasting or after consumption of a standard high-fat meal. There were no significant differences in any pharmacokinetic parameter under the fasting or nonfasting conditions. In the second study, participants received grepafloxacin 400 mg, either alone or after infusion of famotidine 20 mg; additional doses of famotidine were given, if necessary, to maintain intragastric pH above 6. Famotidine treatment had no significant effect on grepafloxacin pharmacokinetics. The results of these studies indicate that neither food nor the elevation of gastric pH influence the absorption or bioavailability of grepafloxacin. Therefore, grepafloxacin can be administered with or without food.

Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers.

OBJECTIVE: The objective of these studies was to examine the clinical pharmacokinetics and safety of zanamivir, an influenza A and B virus neuraminidase inhibitor, when administered to healthy volunteers. DESIGN: The safety, tolerability and pharmacokinetics of zanamivir administered by a number of routes were assessed in randomised, double-blind and placebo-controlled studies. The study of absolute oral bioavailability had an open design. STUDY PARTICIPANTS: The participants in these studies were healthy male or female volunteers. INTERVENTIONS: Zanamivir was administered as single or multiple doses by the intravenous, oral, inhaled (nebuliser and dry powder) and intranasal routes. Serum and urine samples were obtained for determination of pharmacokinetic parameters, and nasal washes and throat gargles were performed to assess drug concentrations in the nose and throat. Safety was evaluated by monitoring adverse events, vital signs and laboratory parameters. RESULTS: Zanamivir was well tolerated at all doses by all routes; no serious adverse events were reported. The kinetics of zanamivir were linear with single intravenous doses up to 600 mg, and there was no evidence of modification in the kinetics after repeated twice-daily administration. Approximately 90% of zanamivir was excreted unchanged in the urine. The elimination of zanamivir from the serum was a first-order process with a half-life of approximately 2 hours and, at 16 L, the volume of distribution was similar to that of extracellular water. The absolute oral bioavailability of zanamivir was low, averaging 2%. After intranasal or oral inhaled administration, a median of 10 to 20% of the dose was systemically absorbed, with maximum serum concentrations generally reached within 1 to 2 hours. The median serum half-life ranged between 2.5 and 5.05 hours, suggesting that the elimination rate is limited by absorption. There was no evidence of modification in the kinetics after repeated inhaled administration. CONCLUSIONS: Zanamivir is a well tolerated drug. The low level of absorption of the drug after inhaled administration results in low serum concentrations, and therefore there is modest systemic exposure to zanamivir after inhalation. Zanamivir is not metabolised, and the potential for clinically relevant drug-drug interactions is very low.

Effect of renal impairment on the pharmacokinetics of grepafloxacin.

Grepafloxacin is mainly (approximately 90%) excreted by nonrenal mechanisms. The effect of renal impairment on the pharmacokinetics of grepafloxacin was evaluated in an open-label study involving 20 adults, 15 of whom had some degree of renal impairment (creatinine clearance 7.5 to 64.0 ml/min). Of these 15, 3 had mild renal impairment, 6 had moderate renal impairment, and 6 had severe renal impairment. Grepafloxacin 400 mg was administered orally once daily for 7 days, and pharmacokinetic parameters were measured on days 1 and 7. The results show that both renal clearance and the amount of grepafloxacin excreted unchanged in urine, on day 1 and day 7, were significantly lower in individuals with severe renal impairment compared with those who were healthy. Renal clearance was 0.50 +/- 0.05 ml/min/kg in healthy individuals vs 0.15 +/- 0.05 ml/min/kg in patients with severe renal impairment on day 1, while the corresponding values on day 7 were 0.46 +/- 0.04 ml/min/kg vs 0.14 +/- 0.08 ml/min/kg, respectively. The percentage of grepafloxacin excreted unchanged in urine on day 1 was 5.1 +/- 3.0 in the healthy individuals and 1.5 +/- 0.7 in those with severe renal impairment. On day 7, the corresponding values were 7.9 +/- 1.9 and 2.9 +/- 2.2. No other significant pharmacokinetic differences occurred between the 2 groups. Accumulation during multiple dose administration did not vary with the degree of renal impairment. We conclude that the pharmacokinetics of grepafloxacin are not significantly different in individuals with varying degrees of renal impairment. Hence, dose adjustment is not necessary during treatment of patients with renal dysfunction.

Theophylline and warfarin interaction studies with grepafloxacin.

Two phase I trials, each involving 16 healthy adult volunteers, were performed to investigate possible interactions between grepafloxacin and theophylline or warfarin. In the theophylline study, grepafloxacin 600 mg was administered once daily for 10 days to 12 volunteers who were receiving a maintenance dose of theophylline. This dose of theophylline was designed to produce mean serum theophylline concentrations of 7.5 mg/L; 4 volunteers received theophylline plus placebo. Pharmacokinetic parameters of theophylline were determined before grepafloxacin treatment and on day 10 of grepafloxacin or placebo administration. Peak theophylline concentrations and the area under the concentration-time curve increased significantly during grepafloxacin treatment, and apparent total clearance of theophylline was reduced by approximately 50%. No changes were observed in the placebo group and theophylline appeared to have no effect on the pharmacokinetics of grepafloxacin. In the warfarin study, grepafloxacin 600 mg was given once daily for 14 days to volunteers receiving a maintenance dose of warfarin. Warfarin was discontinued during the last 4 days of grepafloxacin administration. The pharmacodynamics of warfarin did not change after administration of grepafloxacin. Similarly, warfarin had no significant effect on the pharmacokinetics of grepafloxacin. We conclude that during treatment with grepafloxacin maintenance, doses of theophylline should be reduced by 50%, and we recommend that serum concentrations of theophylline be monitored during treatment with grepafloxacin. However, no dose adjustment is necessary for grepafloxacin when it is coadministered with theophylline, and dose adjustment does not seem to be required in concomitant treatment with grepafloxacin and warfarin.

Effect of renal impairment on the pharmacokinetics of intravenous zanamivir.

OBJECTIVE: Zanamivir is eliminated almost exclusively by renal excretion. This study evaluated the effect of renal impairment on the pharmacokinetics of intravenous zanamivir. DESIGN: This open-label study compared individuals with mild/moderate or severe renal impairment, as defined by creatinine clearance (CLCR), with healthy participants. STUDY PARTICIPANTS: There were 17 participants (9 men and 8 women), of whom 7 had normal renal function (CLCR > 70 ml/min), 5 had mild/moderate renal impairment (CLCR 25 to 70 ml/min) and 5 had severe renal impairment (CLCR < 25 ml/min). INTERVENTIONS: Single 4 mg doses of zanamivir were administered intravenously to healthy participants and those with mild/moderate renal impairment; participants with severe renal impairment received 2 mg. Zanamivir concentrations were determined in blood and urine. Safety was evaluated by monitoring adverse events, vital signs and laboratory parameters. RESULTS: Zanamivir was well tolerated both in participants with renal impairment and in healthy volunteers. There were no clinically significant changes attributable to zanamivir treatment. Renal dysfunction had marked effects on the pharmacokinetics of zanamivir. Although no statistically significant differences were detected between either renal impairment group and the normal renal function group for the maximum serum concentration (Cmax) or the time this occurred (tmax), a strong relationship was detected between CLCR and total body clearance (CL), renal clearance (CLR) and the terminal phase elimination rate constant (lambda z). Each 2-fold increase in CLCR produced average increases of 100, 121 and 85% in CL, CLR and lambda z, respectively. The area under the serum concentration-time curve from zero to infinity (AUC infinity) was on average increased 2-fold in individuals with mild/moderate renal impairment (4 mg dose) and 3.5-fold in those with severe impairment (2 mg dose) compared with healthy individuals (4 mg dose). CONCLUSIONS: The proposed total daily dosage of zanamivir by oral inhalation is 20 mg. Given the tolerability (observed in a separate study to be reported in this supplement) after daily intravenous dosages of 1200 mg, and the limited systemic absorption after oral inhalation, the increased drug exposure in patients with severe renal failure is not considered clinically significant. Furthermore, the local concentrations in the lung following oral inhaled delivery are essential for efficacy. Therefore, for orally inhaled zanamivir, no dosage adjustment is required in patients with renal impairment.

Grepafloxacin pharmacokinetics in individuals with hepatic dysfunction.

The pharmacokinetics of grepafloxacin, a new broad spectrum fluoroquinolone antibiotic, were studied in 2 trials involving 14 healthy volunteers, 10 individuals with mild (Child-Pugh Class A) impairment of liver function, and 12 with moderate (Child-Pugh Class B or C) hepatic impairment. All participants received an oral dose of grepafloxacin 400 mg, daily for 7 days, and plasma and urine grepafloxacin concentrations were measured over 7 days. The pooled data from participants with impaired liver function showed that, compared with healthy individuals, peak plasma grepafloxacin concentrations, area under the plasma concentration-time curve and proportion of the dose excreted in the urine were increased. In addition, apparent total clearance was reduced in the presence of hepatic dysfunction. Peak concentrations were increased by 36% and 48% in individuals with Class A and B disease, respectively; the corresponding reductions in clearance were 33% and 55%, respectively. Child-Pugh scores and components of the scores showed no correlation with any pharmacokinetic variables. Based on these findings, we recommend a daily grepafloxacin dose of 400 mg in patients with mild hepatic impairment, irrespective of the severity of infection. Grepafloxacin should not be used in patients with moderate or severe liver disease.

Concentration of cefuroxime in middle ear effusion of children with acute otitis media.

BACKGROUND: Antibiotic concentrations in serum and middle ear effusion are important in determining therapeutic success in acute otitis media. For beta-lactams the most relevant pharmacokinetic index for clinical efficacy is the time for which serum concentrations exceed the minimum inhibitory concentration (MIC) of the pathogen, which should be at least 40 to 50% of the dosing interval. METHODS: In this open, single center study, the concentration of cefuroxime achieved in the serum and middle ear effusion of pediatric acute otitis media patients with purulent effusion was assessed between 2 and 5 h after a single oral dose of 15 mg/kg cefuroxime axetil suspension. RESULTS: Serum concentrations of cefuroxime ranged from 2.8 to 7.3 microg/ml and were consistent with the results of previous pharmacokinetic study. These results show that serum concentrations of cefuroxime remain above the MIC90 (2.0 microg/ml) for Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis for at least 5 h (42%) of the 12-h dosing interval. Cefuroxime was detected in 14 of 17 (82%) middle ear effusion samples and ranged from 0.2 to 3.6 microg/ml, indicating that cefuroxime penetrates well into the middle ear. CONCLUSIONS: Cefuroxime is well-absorbed and penetrates well into the middle ear after oral administration of cefuroxime axetil suspension.

Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study.

The pharmacokinetics and metabolism of 4-demethoxydaunorubicin (idarubicin, IDA) were studied in 21 patients with advanced cancer after i.v. (12 mg/m2) and oral (30-35 mg/m2) treatment according to a balanced crossover design. Patients were divided into four groups: subjects who showed normal liver and kidney function (group N), those who presented with normal kidney function and liver metastases (group L), those with kidney dysfunction (creatinine clearance, less than or equal to 60 l/h; group R), and those with both liver and kidney dysfunction (group LR). Five patients showed variations in liver or kidney function after the first treatment and were considered to be nonevaluable for the crossover study but evaluable for the liver/kidney function study; some of them appeared in different groups for the i.v. as opposed to p.o. treatments. After i.v. administration, IDA plasma levels followed a triphasic decay pattern. The main metabolite observed in all patients was the 13C-reduced compound (IDAol), which attained plasma levels 2-12 times higher than those of the parent compound. IDA pharmacokinetics was not dependent on the presence of liver metastases but was related to the integrity of kidney function. Analysis of variance indicated a significant correlation between IDA plasma clearance and creatinine clearance; it was also found that IDA plasma clearance was lower in patients whose creatinine clearance was less than 60 ml/min [group N, 122.8 +/- 44.0 l/h; group L, 104.4 +/- 27.7 l/h (P = 0.58) vs group R, 83.4 +/- 18.3 l/h (P = 0.037)]. The IDAol terminal half-life and mean residence time (MRT) were significantly increased in patients with impaired kidney function [MRT: group N, 63.6 +/- 10.8 h; group L, 69.9 +/- 10.2 h (P = 0.27) vs group R, 83.2 +/- 10.9 h (P = 0.025) and t1/2 gamma: group N, 41.3 +/- 10.1 h; group L, 47.0 +/- 7.4 h (P = 0.31) vs group R, 55.8 +/- 8.2 h (P = 0.025)]. After oral treatment, drug absorption occurred during in the first 2-4 h after IDA administration; a biphasic decay pattern was observed thereafter. The main metabolite observed in all patients was again IDAol. The AUC of IDAol was greater after oral administration than after i.v. treatment in proportion to the AUC of IDA (i.v.: AUC-IDAol/AUC-IDA, 2.4-18.9; p.o.: AUC-IDAol/AUC-IDA, 4.1-21.4). Following oral dosing, a substantial amount of 4-demethoxydaunomycinone (AG1) was found in 11/21 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

In vivo interaction of cabergoline with rat brain dopamine receptors labelled with [3H]N-n-propylnorapomorphine.

Cabergoline is a potent dopaminergic agent that interacts with agonists and antagonists of dopamine receptors in vitro. We studied the binding of [3H]N-n-propylnorapomorphine ([3H]NPA) to dopamine receptors after i.v. and oral administration of cabergoline to determine whether cabergoline crosses the blood-brain barrier; bromocriptine was used as a reference drug. Cabergoline and/or its active metabolite(s) did cross the blood-brain barrier and reach dopamine receptors. Comparative time-course analysis of the regional inhibition of [3H]NPA binding showed that cabergoline was more potent than bromocriptine in inhibiting [3H]NPA binding and that it occupied the receptor for longer. These effects were observed in all areas of the rat brain studied (striatum, olfactory tubercles, adeno- and neurohypophysis, thalamus and hypothalamus). Further studies in the striatum and adenohypophysis showed that cabergoline receptor occupancy was dose-dependent and still detectable 72 h after i.v. administration of the drug. While cabergoline was more potent in the striatum than in the adenohypophysis when administered i.v., the reverse was observed after its oral administration. Cabergoline was equally potent in the adenohypophysis after oral and i.v. administration, as determined 1 and 8 h later.

Improved bioavailability of a new oral preparation of medroxyprogesterone acetate.

Medroxyprogesterone acetate (MPA) is widely used in the hormonal therapy of breast cancer. So far, oral formulations of MPA commercially available present a very low bioavailability, with a less than 10% extent of oral absorption. A new oral preparation of MPA has been recently developed. Based on a pilot study, an open, randomized, crossover trial has been performed on 22 breast and endometrial cancer patients to evaluate the relative bioavailability of this new oral formulation (200-mg sachet, twice daily) as compared with a standard formulation (Farlutal, 500-mg tablet, twice daily). The bioavailability evaluation was mainly based on the area under the curve measured between two administrations at steady state, after 15 days of continuous therapy. Wide interpatient variability of MPA plasma levels after oral MPA administration was confirmed. The MPA plasma levels were higher in patients treated with the new formulation than in patients treated with Farlutal. The relative bioavailability of the new preparation was 3.5 times higher than that of the standard. This new formulation represents a great improvement in the extent of oral absorption of MPA and could lead to better management of hormone-responsive tumors by hormonal therapy.

A pharmacokinetic model for multiple sites discontinuous gastrointestinal absorption.

PURPOSE: To build a pharmacokinetic model taking into account a discontinuous absorption along the gut, from n successive sites, a non-absorbing intestinal segment being always in between two successive sites. To solve the mathematical model linked with the pharmacokinetic model to obtain the concentration and contribution of each site to absorption, area under curve and bioavailability. METHODS: Whatever the number n of sites, we obtained the Laplace transform of amounts of drug in each site, then plasma concentration, so that concentration or AUC were expressed analytically. When only two absorption sites are present, concentration is obtained from Heaviside's theorem; but for n> or =3, Bromwich's theorem is necessary, a pole being of the order of more than two. RESULTS: Simulations performed with data gathered from the literature allow to find, with n=2 sites, the particular case used for ranitinine and to show the efficacy of each site. For n=3 sites, real data exhibiting three peaks of various magnitude were fitted on our model. CONCLUSION: This general discontinuous oral absorption pharmacokinetic model may be taken as a possible tool to characterize each site of absorption and to estimate the area under curves or bioavailability.

A study of the effects of rifabutin on isoniazid pharmacokinetics and metabolism in healthy volunteers.

The effect of repeated administration of rifabutin on the pharmacokinetics and metabolism of isoniazid was evaluated in 6 healthy volunteers. The subjects received on day 1 and 9 a single oral dose of 300 mg isoniazid and from day 2 to 8 a single daily oral dose of 300 mg rifabutin. Two out of 6 subjects were shown to be rapid acetylators. No significant modification of the plasma pharmacokinetic profiles of isoniazid and acetylisoniazid was found. Evidence exists in the present study for autoinduction of rifabutin metabolism; this is shown by the lower plasma concentrations obtained 24 h after the seventh dose as compared to the theoretical concentrations.

Pharmacokinetics of acipimox and of its N-deoxy metabolite following single and repeated oral administration to healthy volunteers.

The aim of the present study was to evaluate the plasma pharmacokinetics of acipimox and of its N-deoxy metabolite (5-methylpyrazine-2-carboxylic acid, MPCA) following single and repeated administration of 250 mg acipimox (thrice daily, for 6 days) to ten healthy volunteers. Mean maximum concentration, the corresponding time, area under the curve extrapolated to infinity and elimination half-life values of acipimox after single administration were equal to 5.74 micrograms/ml (range 2.56-8.38 micrograms/ml), 1.7 h (1-3 h), 16.99 micrograms/ml.h (11.28-22.17 micrograms/ml.h) and 1.15 h (0.79-1.48 h), respectively. Mean area under the curve over one dosing interval (8 h) and elimination half-life values of acipimox after repeated dosing were not significantly different from the corresponding values after the single dose. No significant accumulation was observed following the repeated treatment, since the mean accumulation ratio was 1.08 (range 0.74-1.52). The mean maximum concentration and corresponding time values in the 7 out of 10 subjects with detectable metabolite levels after the single dose were 0.19 microgram/ml (0.10-0.34 microgram/ml) and 6.7 h (3-12 h), respectively, whilst after the repeated treatment, detectable concentrations of the metabolite were observed in all subjects, the mean maximum concentration value being equal to 0.48 micrograms/ml (0.11-1.19 microgram/ml). The average ratio of the parent/metabolite area under the curve values (8 h) after repeated dosing was equal to 14 (range 2-56). Inter-subject variability in the extent of metabolite formation was very high.

Energy localization on q-tori, long-term stability, and the interpretation of Fermi-Pasta-Ulam recurrences.

We focus on two approaches that have been proposed in recent years for the explanation of the so-called Fermi-Pasta-Ulam (FPU) paradox, i.e., the persistence of energy localization in the "low-q " Fourier modes of Fermi-Pasta-Ulam nonlinear lattices, preventing equipartition among all modes at low energies. In the first approach, a low-frequency fraction of the spectrum is initially excited leading to the formation of "natural packets" exhibiting exponential stability, while in the second, emphasis is placed on the existence of "q breathers," i.e., periodic continuations of the linear modes of the lattice, which are exponentially localized in Fourier space. Following ideas of the latter, we introduce in this paper the concept of " q-tori" representing exponentially localized solutions on low-dimensional tori and use their stability properties to reconcile these two approaches and provide a more complete explanation of the FPU paradox.

Pharmacokinetics of grepafloxacin.

Grepafloxacin is a fluoroquinolone antibiotic which is rapidly absorbed in healthy volunteers following oral dosing. It reaches peak plasma levels around 2 h after administration, then declines bi-exponentially, with an extended half-life of around 12 h. Grepafloxacin is eliminated primarily through metabolism and is excreted mainly in the faeces. Renal clearance accounts for only 10-15% of the administered dose. Grepafloxacin plasma concentrations increase disproportionately with increasing doses, but this is unlikely to be of clinical significance over the range of therapeutic doses. The rate and extent of absorption are not affected by food or elevated intragastric pH. The pharmacokinetics of grepafloxacin are affected by gender, with these differences relating to variations in body weight. No effect of age on the pharmacokinetics of grepafloxacin was found. Renal impairment does not affect grepafloxacin pharmacokinetics, whereas peak plasma concentrations, areas under plasma concentration-time curves and renal excretion are increased in patients with hepatic impairment. Grepafloxacin can be co-administered with warfarin and theophylline, though reduction of the theophylline dose is necessary. Following oral administration, higher grepafloxacin concentrations are achieved in lung and genital tissues than in serum, indicating its potential in the treatment of respiratory and sexually transmitted diseases. In addition, it exceeds therapeutically effective levels in bile and gall-bladder tissues, and accumulates in polymorphonuclear leucocytes such that it may be useful against intracellular pathogens.