Wind Generated Rogue Waves in an Annular Wave Flume.

We investigate experimentally the statistical properties of a wind-generated wave field and the spontaneous formation of rogue waves in an annular flume. Unlike many experiments on rogue waves where waves are mechanically generated, here the wave field is forced naturally by wind as it is in the ocean. What is unique about the present experiment is that the annular geometry of the tank makes waves propagating circularly in an unlimited-fetch condition. Within this peculiar framework, we discuss the temporal evolution of the statistical properties of the surface elevation. We show that rogue waves and heavy-tail statistics may develop naturally during the growth of the waves just before the wave height reaches a stationary condition. Our results shed new light on the formation of rogue waves in a natural environment.

Three unrelated sphingomyelin analogs spontaneously cluster into plasma membrane micrometric domains.

Micrometric lipid compartmentation at the plasma membrane is disputed. Using live confocal imaging, we found that three unrelated fluorescent sphingomyelin (SM) analogs spontaneously clustered at the outer leaflet into micrometric domains, contrasting with homogeneous labelling by DiIC18 and TMA-DPH. In erythrocytes, these domains were round, randomly distributed, and reversibly coalesced under hypotonicity. BODIPY-SM and -glucosylceramide showed distinct temperature-dependence, in the same ranking as Tm for corresponding natural lipids, indicating phase behaviour. Scanning electron microscopy excluded micrometric surface structural features. In CHO cells, similar surface micrometric patches were produced by either direct BODIPY-SM insertion or intracellular processing from BODIPY-ceramide, ruling out aggregation artefacts. BODIPY-SM surface micrometric patches were refractory to endocytosis block or actin depolymerization and clustered upon cholesterol deprivation, indicating self-clustering at the plasma membrane. BODIPY-SM excimers further suggested clustering in ordered domains. Segregation of BODIPY-SM and -lactosylceramide micrometric domains showed coexistence of distinct phases. Consistent with micrometric domain boundaries, fluorescence recovery after photobleaching (FRAP) revealed restriction of BODIPY-SM lateral diffusion over long-range, but not short-range, contrasting with comparable high mobile fraction of BODIPY-lactosylceramide in both ranges. Controlled perturbations of endogenous SM pool similarly affected BODIPY-SM domain size by confocal imaging and its mobile fraction by FRAP. The latter evidence supports the hypothesis that, as shown for BODIPY-SM, endogenous SM spontaneously clusters at the plasmalemma outer leaflet of living cells into ordered micrometric domains, defined in shape by liquid-phase coexistence and in size by membrane tension and cholesterol. This proposal remains speculative and calls for further investigations.

Statistical properties of directional ocean waves: the role of the modulational instability in the formation of extreme events.

We discuss two independent, large scale experiments performed in two wave basins of different dimensions in which the statistics of the surface wave elevation are addressed. Both facilities are equipped with a wave maker capable of generating waves with prescribed frequency and directional properties. The experimental results show that the probability of the formation of large amplitude waves strongly depends on the directional properties of the waves. Sea states characterized by long-crested and steep waves are more likely to be populated by freak waves with respect to those characterized by a large directional spreading.

Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans.

Loperamide oxide (LOPOX) is a prodrug of loperamide (LOP). The reduction of LOPOX to LOP was investigated to provide a pharmacokinetic basis for the pharmacodynamics and improved side effect profile of the prodrug. Reduction of LOPOX was studied in vitro in gut contents, gut flora, intestinal cells, and hepatocytes. In vivo pharmacokinetics and metabolism of LOPOX and LOP were compared in the dog. LOPOX could be efficiently reduced in the gut contents of rats, dogs, and humans, with the most extensive reduction found in cecal contents. Reduction was diminished to 13% of the anaerobic LOPOX reductase activity in the presence of oxygen and to 2.5% of the original activity by heat treatment of the contents. In human ileal effluents, LOPOX reductase activity was similar in oxygen and heat sensitivity. In the rat, the cecum contained on average 89.2% of the total activity in the contents of the upper part of the intestine. In the dog, there was a gradual increase in LOPOX reductase activity from the proximal small intestine toward the cecum. In germ-free rats, the cecum contained < 1% of the activity of the small intestine. Isolated intestinal microflora of rat and dog was able to reduce LOPOX to LOP under anaerobic conditions, indicating that the microflora was primarily involved in the reduction. In its absence (i.e. in germ-free rats), reduction could still be conducted by other unknown components of the gut contents. In isolated intestinal cells, the initial rate of drug uptake was approximately 3-10 times faster for LOP than for LOPOX.(ABSTRACT TRUNCATED AT 250 WORDS)

Study of the placental transfer of cisapride in sheep. Plasma levels in the pregnant ewe, the fetus, and the lamb.

The placental transfer of cisapride, a new prokinetic agent, was studied in a sheep model. The pharmacokinetics of cisapride were studied in the lamb, the pregnant ewe, and the fetus by obtaining blood samples from chronically implanted arterial catheters. Comparable pharmacokinetic parameters were found in the lamb and the adult sheep: half-life, 1.39-1.83 hr; total plasma clearance, 1998-2160 ml/kg/hr; AUC, 92.6-100.1 ng.hr/ml. Cisapride plasma concentrations after continuous infusion were predicted correctly based on the parameters obtained after iv bolus. There was a materno-fetal transfer of cisapride following a single iv bolus administered to the mother. Cisapride crossed the placenta within 5 min and equilibrated with maternal plasma within 20 to 30 min after dosing. The average fetal-to-maternal plasma concentration ratio was 0.71. The amniotic fluid also contained measurable amounts of cisapride. The protein binding of cisapride in maternal and fetal plasma is 89.0% and 88.4%, respectively; the free fraction is 4 times larger than in humans. Cisapride crosses the ovine placental barrier. The sheep placenta is less permeable than the human placenta, but the higher free fraction of cisapride facilitates placental transfer.

Effects of cytochrome P-450 inhibitors on the in vivo metabolism of all-trans-retinoic acid in rats.

This study examines the effects of ketoconazole, R 75 251 and some other cytochrome P-450 inhibitors on the in vivo metabolism of all-trans-retinoic acid (RA) in normal rats. Oral treatment with ketoconazole or R 75 251 (40 mg/kg, -1 hr) reduced the elimination rate of i.v. injected RA from plasma: the half-life of RA increased from 27 min in control-treated animals to 43 min and 76 min after dosing with ketoconazole and R 75 251, respectively. However, neither drug had an effect on the distribution volume of the retinoid. Two hours after i.v. injection of RA, residual plasma levels of the retinoid were 11.2 ng/ml in ketoconazole and 22.7 ng/ml in R 75 251-treated rats. The other P-450 inhibitors, aminoglutethimide, cimetidine, itraconazole, metyrapone and saperconazole, showed no sparing effect on RA elimination: plasma levels of the acid were below 1 ng/ml, as in control-treated animals. Administration of ketoconazole or R 75 251 (40 mg/kg, -2 hr) to rats also enhanced endogenous plasma concentrations of RA. Levels of the retinoid were raised from mostly undetectable values (less than 0.5 ng/ml) to 1.3 +/- 0.1 and 2.5 0.1 ng/ml after treatment with ketoconazole and R 75 251, respectively. These data are indicative of the important contribution of the cytochrome P-450 enzyme system to the in vivo metabolic process of RA. In vivo inhibition of the P-450 pathway not only increased the biological half-life of exogenously administered RA, but also enhanced the endogenous plasma level of this vitamin A derivative.

Pharmacokinetics and tissue distribution of ketanserin in rat, rabbit and dog.

The plasma kinetics and tissue distribution of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)- quinazolinedione, R 41 468) were studied in the rat, rabbit and dog. The studies were performed utilizing 3H- and 14C-labelled ketanserin and appropriate techniques to measure levels of radioactivity, unchanged drug and a major metabolite ketanserin-ol in plasma and tissues. Following intravenous administration to male rats and dogs (10 mg/kg), plasma levels could be described by a two-compartment model. The plasma clearance (C1) averaged 3.8 and 19.2 ml/min/kg and the volume of distribution (Vdss) 0.67 and 4.7 l/kg in male rats and in dogs, respectively. Following oral administration (10-40 mg/kg), ketanserin was rapidly and completely absorbed in all species studied. The absolute bioavailability of oral ketanserin was more than 80% in both rats and dogs. Due to the high clearance of the metabolites in rats, ketanserin was the main component of the plasma radioactivity. In dogs, the fraction of the metabolite ketanserin-ol was more pronounced than that of ketanserin. The apparent elimination half-life of ketanserin was 1.5 h in rabbits, 2-5 h in rats and 3-15 in dogs. The pharmacokinetics of ketanserin were dose-related after single and chronic intravenous and oral dosing. Distribution studies in rats after intravenous and oral administration (10 mg/kg) demonstrated an almost immediate equilibrium between plasma and tissues, resulting in slightly higher tissue than plasma concentrations in the well perfused tissues, and similar or slightly lower levels in the remaining tissues. Ketanserin was the main component of tissue radioactivity. The drug crossed the blood-brain barrier only to a slight extent, brain levels of the unchanged drug being similar to the free fraction in plasma. Ketanserin disappeared from tissues with a similar half-life to that in plasma. On repeated dosing, a small fraction of metabolites was more slowly eliminated. The excretion of the urinary and faecal metabolites after repeated dosing was very similar to that after a single dose. Placental transfer of ketanserin in the rat was limited. On average 0.3% of the maternal radioactive dose, preferentially metabolites, was recovered from the combined foetuses. In dogs orally treated with doses of up to 40 mg/kg/d for 12 months, no undue accumulation or retention of ketanserin or ketanserin-ol was found in any tissue. In lactating dogs orally dosed at 10 mg/kg, preferentially metabolites were excreted in the milk. Concentrations of ketanserin and ketanserin-ol in the milk were respectively 2 and 4 times higher than plasma levels.

Hypnoanalgesia with R 8110/fentanyl in the dog: pharmacodynamic and pharmacokinetic interactions.

The pharmacokinetics and clinical effects of the short-acting hypnotic R 8110 and of the narcotic analgesic fentanyl were studied in the dog. The effects of separate intravenous (i.v.) injections of R 8110 (4 mg/kg) and fentanyl (0.015 mg/kg) and of concurrent i.v. injection of the two were studied. After administration of R 8110, induction of hypnosis occurred within 1 min, maximal depth of anaesthesia and satisfactory analgesia and muscle relaxation were obtained after 5 min. The effects had decreased within 15 min and full recovery occurred within 30 min. Fentanyl alone produced neither hypnosis nor muscle relaxation. When fentanyl and R 8110 were given simultaneously, the duration of hypnosis was doubled in comparison with R 8110 alone. Moreover, markedly improved and longer lasting analgesia and muscle relaxation were observed with the combination. When the drugs were injected together, the plasma concentrations of R 8110 were initially much higher than after separate injection of R 8110, but they became similar after 30 min. Although statistically non-significant, fentanyl reduced the total plasma clearance of R 8110 (31.1 +/- 6.9 vs. 21.9 +/- 2.3 ml/kg/min) and decreased the volume of distribution (3.78 +/- 1.83 vs. 2.23 +/- 0.90 l/kg, P less than 0.05). Fentanyl did not alter the elimination half-life of R 8110. R 8110 had no apparent influence on the pharmacokinetics of fentanyl.

Study of the bioavailability of different formulations of 8-methoxypsoralen in the dog.

The absolute bioavailability of 8-methoxypsoralen in gelatin capsules and as a solution was studied in dogs. A dose of 2 mg kg-1 was given. Both for the solution and the gelatin capsules, a large variation in bioavailability was found between the different dogs. For the gelatin capsules in 1 dog out of 4 an absolute bioavailability of more than 100 per cent was found; for the solution a bioavailability of more than 100 per cent was found in all 4 dogs. Resorption was more rapid and bioavailability higher for the solution than for the gelatin capsules. Relative bioavailability of an emulsion and of a solution of 8-methoxypsoralen was studied in 2 dogs. A faster resorption and a higher bioavailability were found for the solution.

Pharmacokinetics of 8-methoxypsoralen in the dog.

The pharmacokinetics of 8-MOP were studied in six dogs following intravenous administration of 2 mg kg-1. In most animals a bi-exponential decline of the plasma level profile was observed. The calculated pharmacokinetic parameters varied considerably between the different dogs. The mean half-lives of distribution and of elimination were 0.20 and 2.17 h, respectively. The average total plasma clearance was 0.51 l kg-1 h-. Following both oral and intravenous administration of doses of 1, 3, and 10 mg kg-1, non-linear kinetics were found. Non-linearity was confirmed following administration of the substance at increasing infusion rates. Finally in four dogs, extraction by the liver was calculated by measuring 8-MOP concentration in the femoral artery and in a hepatic vein after intravenous administration of 1 mg kg-1. The extraction varied from animal to animal (18 per cent to nearly 100 per cent). Administration of an additional dose of 3 mg kg-1 in two of the dogs led to a decreased extraction.

Pharmacokinetics and tissue distribution of the new gastrokinetic agent cisapride in rat, rabbit and dog.

The plasma kinetics and tissue distribution of the gastrokinetic (+/-)-cis-4-amino-5-chloro-N-[1-(3-(4-fluorophenoxy)propyl]-3-methoxy-4- piperidinyl]-2-methoxybenzamide monohydrate (cisapride, R 51 619) have been studied in the rat, rabbit and dog. After intravenous administration to rats (5 mg/kg) and dogs (0.63 mg/kg) plasma level-time curves were adequately fitted to a two-compartmental model. The plasma clearance (ClT) and volume of distribution (Vdss) averaged 91 ml/min.kg and 4.7 l/kg in the rat and 4.2 ml/min.kg and 0.82 l/kg in the dog, respectively. Following oral administration, cisapride was rapidly and almost completely absorbed from the gastrointestinal tract in rats and rabbits. The absorption was somewhat slower in the dog. In male rats the plasma radioactivity was mainly due to metabolites, unaltered cisapride representing on average 10% of the total radioactivity. A markedly larger proportion of the parent drug was seen in female rats. Linear plasma kinetics were observed for cisapride in the dose range of 10 to 160 mg/kg. Similarly in the dog, linearity was observed after oral administration in the range of 0.31 to 10 mg/kg. The plasma kinetics remained unaltered on repeated oral doses of 10 mg/kg to rats and subchronic intravenous administration at 0.63 mg/kg to dogs. Compared with intravenous administration, the absolute bioavailability of oral cisapride was 23% in rats and 53% in the dog for the drug given in solution. The terminal plasma half-life of cisapride was about 1-2 h in the rat and about 4-10 h in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Methoxypsoralen plasma levels and phototoxic effect.

In 8 normal volunteers, the minimal phototoxic dose was determined at 15 min intervals up to 60 min and thereafter every 30 min up to 4 h; 8-methoxypsoralen (8-MOP) was administered as a solution and small additional doses were given during the course of the experiment, so that a more or less predictable and stable plasma concentration was obtained and maintained for about 2 h. Three of the subjects absorbed 8-MOP very rapidly, already reaching plasma concentrations above 200 ng/ml after 15 min; in the other 5, absorption was slower and comparable levels were achieved only after 30 to 90 min. In the fastest absorbers, there was a 15 to 30 min lag between reaching a high plasma level and a low MPD. In the other cases, such a delay was not seen. This suggests that the time to reach peak concentration in the skin is not influenced by changes in absorption rate: simulations based on the classical plasma concentration equations for a two-compartmental model also show this. Afterwards, the skin sensitivity decreased in most cases parallel to the plasma concentrations.

[Relation between plasma levels of 8-methoxypsoralen and the phototoxic effect]. / Relations entre les taux plasmatiques du 8-méthoxypsoralène et l'effet phototoxique.

Plasma concentrations of 8-MOP were studied in 6 subjects at three dose levels and the minimal phototoxic dose determined after 60, 120 and 180 min. Although there is an inverse correlation between these two values, none of the eight mathematical expressions examined gave a perfect fit in all cases.

Analysis of methoxsalen in plasma by reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of methoxsalen in plasma was developed. The method includes extraction from plasma of the drug and the internal standard (5-methoxypsoralen) into methylene chloride. Chromatography was performed on a reversed-phase C8 column connected with a UV detector set at 254 nm. The mobile phase was methanol-acetonitrile-water (2:30:68). For a plasma sample of 0.25 ml, the maximal sensitivity was approximately 10 ng/ml. Accuracy was within 7.5% for therapeutic plasma levels, and the coefficient of variation varied between 4.3 and 0.9% for 28 and 300 ng/ml of plasma, respectively.

Problems with commercial formulations of 8-methoxypsoralen.

Plasma concentrations of 8-methoxypsoralen were measured in 8 psoriatic patients after administration of two commercial solid formulations and of an 8-methoxypsoralen solution. Systemic availability as measured by the area under the concentration versus time curve was much higher for the solution than for the two commercial formulations. For the solid formulations, a large inter- and intraindividual variation in plasma concentrations was found and in many cases no plasma levels could be measured. Administration of the solution gave always more reproducible plasma concentrations in function of time.