Constraint of the Nuclear Dissipation Coefficient in Fission of Hypernuclei.

Experimental studies of nuclear fission induced by fusion, transfer, spallation, fragmentation, and electromagnetic reactions in combination with state-of-the-art calculations are successful to investigate the nuclear dissipation mechanism in normal nuclear matter, containing only nucleons. The dissipation mechanism has been widely studied by the use of many different fission observables and nowadays the dissipation coefficients involved in transport theories are well constrained. However, the existence of hypernuclei and the possible presence of hyperons in neutron stars make it necessary to extend the investigation of the nuclear dissipation coefficient to the strangeness sector. In this Letter, we use fission reactions of hypernuclei to constrain for the first time the dissipation coefficient in hypernuclear matter, observing that this coefficient increases a factor of 6 in the presence of a single Λ hyperon with respect to normal nuclear matter.

Bioindicators of severe ocean acidification are absent from the end-Permian mass extinction.

The role of ocean acidification in the end-Permian mass extinction is highly controversial with conflicting hypotheses relating to its timing and extent. Observations and experiments on living molluscs demonstrate that those inhabiting acidic settings exhibit characteristic morphological deformities and disordered shell ultrastructures. These deformities should be recognisable in the fossil record, and provide a robust palaeo-proxy for severe ocean acidification. Here, we use fossils of originally aragonitic invertebrates to test whether ocean acidification occurred during the Permian-Triassic transition. Our results show that we can reject a hypothesised worldwide basal Triassic ocean acidification event owing to the absence of deformities and repair marks on bivalves and gastropods from the Triassic Hindeodus parvus Conodont Zone. We could not, however, utilise this proxy to test the role of a hypothesised acidification event just prior to and/or during the mass extinction event. If ocean acidification did develop during the mass extinction event, then it most likely only occurred in the latest Permian, and was not severe enough to impact calcification.

Evaluation of the gastric absorption and emptying of drugs under various pH conditions using a simple intubation method: application to diclofenac.

Sodium diclofenac (50 mg) together with [14 C]-PEG as a non-absorbable marker were dissolved in 400 ml of water (A), phosphate buffer pH 7.5 (B) or a homogenized meal (C). Each of these was ingested in random order by six volunteers on 3 consecutive days. Some gastric absorption of the drug was established with C but the plasma drug concentration-time profiles mainly reflected the process of gastric emptying.

Jejunal and ileal absorption of oxprenolol in man: influence of nutrients and digestive secretions on jejunal absorption and systemic availability.

1 Study I evaluated the absorption of oxprenolol in the ileum, compared to jejunum, in healthy volunteers by an intestinal perfusion technique. Around 80 mg of drug were delivered as a saline solution directly in the small bowel. 2 Samples taken 30 cm distally to the site of perfusion showed that 63% of perfused oxprenolol was absorbed in the jejunum and 48% in the ileum; the differences were significant. 3 The plasma concentration-time profiles were similar for the two perfusions. The AUC and Cmax values of free and conjugated oxprenolol for the jejunal perfusion were significantly lower than those of ileum. They showed large but consistent intersubject variations in the two treatments. 4 Study II investigated, using the same technique, the influence of nutrients and digestive secretions on jejunal absorption and systemic availability of this drug. A saline (in treatments A and B) or a nutrient (in treatment C) solution containing oxprenolol was perfused into the jejunum below a balloon either inflated (A) or deflated (B and C). 5 The disappearance rate of oxprenolol from the jejunum was unaffected by endogenous secretions. The mean amount of drug absorbed along a 30-cm jejunal segment accounted for 52 (A) and 57% (B) of the total amount perfused. The intestinal absorption rate was markedly increased in the presence of nutrients (mean amount absorbed 96% for C). 6 The change in the rate of disappearance from the intestine had no effect on the systemic availability of oxprenolol (mean AUC values 8740, 8250 and 8020 nmol l-1 h for A, B and C, respectively) or its elimination from plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

[Vidarabine treatment of chronic active hepatitis associated with hepatitis B virus multiplication. A randomized multicenter study]. / Traitement par la vidarabine de l'hépatite chronique active associée à la multiplication du virus de l'hépatite B. Etude multicentrique randomisée.

A randomized controlled study of one course of vidarabin was carried out in 30 patients with HBs Ag, HBe Ag, DNAp, positive chronic active hepatitis: 15 patients were treated with vidarabin given intravenously (15 mg/kg/day for 7 days then 7.5 mg/kg/day for 14 days); the other 15 patients received a placebo for 21 days. During treatment, DNA polymerase activity fell dramatically in 13 treated patients and in no controls (p less than 0.001). Six months after inclusion, ALT normalization was observed in 40 p. 100 of the treated patients and 6 p. 100 of the controls (p less than 0.05), a decrease in inflammatory activity on liver biopsies was observed in 70 p. 100 of the treated patients and 20 p. 100 of the controls (p less than 0.05), a permanent lost of DNA polymerase and of HBe Ag occurred in 33 p. 100 and 13 p. 100 of the treated patients and 20 p. 100 and 7 p. 100 of the controls, respectively. In addition, a second course of vidarabin was administered to the 12 patients who were still HBe Ag positive 6 months after the first course. During the next 6 months, 8 patients lost DNA polymerase and 4 lost HBe Ag. Altogether, the final score of durable inhibition of HBV replication was 11/15 (73 p. 100) within one year. The above results demonstrate that one course of vidarabin can significantly improve ALT and liver inflammatory activity but the effect upon HBV replication is only transient. A second course does however increase efficacy on HBV replication without additional side effects.

Gastric and intestinal absorption of oxprenolol in humans.

The gastrointestinal absorption of the beta blocker oxprenolol was investigated in four healthy subjects by an intubation technique. Oxprenolol was introduced into the stomach, dissolved in a homogenized meal containing the marker 14C-polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was perfused during the whole experiment into the duodenum at the ampulla of Vater. Samples of luminal contents were collected at regular intervals over four hours in the stomach, at the angle of Treitz, and 30 cm below this point. Blood was also collected. Oxprenolol was not absorbed in the stomach. About 80% of the drug emptied from the stomach was absorbed in the duodenum, and 80% of that released from the duodenum was absorbed in a 30-cm segment of the jejunum. The amounts absorbed in these two intestinal segments were directly proportional to the amounts delivered. The areas under the plasma concentration-time curves were not related to the amounts absorbed. A single dose of oxprenolol taken with an homogenized meal did not modify the gastric emptying and secretory response.

Importance of analytical methods in pharmacokinetic and drug metabolism studies.

Pharmacokinetic and drug metabolism studies first request that good analytical data are available. The various methods that permit unchanged drugs and their metabolites to be separated, identified and quantitatively assayed are briefly reviewed. The present importance of gas chromatography/mass spectrometry is emphasized, as well as the limits of immunological assays. The sensitivity of the analytical assay has a direct impact on the validity of the pharmacokinetic model which is built up from plasma concentration data. The precision and accuracy of the assay is also critical, and it is not always easily estimated. A new significant parameter is the speed of analysis, and the resulting massive production of analytical data. New drugs coming from biotechnology, and new dosage forms, like targeted drugs, will create new analytical problems in the future. They will probably call for the development of new biological or pharmacological assay procedures, in addition to the physicochemical means of analysis.

The gastrointestinal absorption of drugs in man: a review of current concepts and methods of investigation.

The various mechanisms which have been advanced to explain drug absorption are critically reviewed and the limitations of current theories are discussed. Various techniques for investigating drug absorption and transit through the gut are presented, and the results obtained with metoprolol are briefly considered to illustrate the potential of some of these methods.

Investigation of drug absorption from the gastrointestinal tract of man. II. Metoprolol in the jejunum and ileum.

Absorption of metoprolol in jejunum and ileum was investigated in eight healthy subjects using an intestinal perfusion technique below an occlusive balloon. An isotonic saline solution, with or without metoprolol, was perfused at a flow rate of 10 ml/min, either at the angle of Treitz or in the middle part of the ileum. The absorption in a 30 cm intestinal segment was evaluated at metoprolol concentrations of 20, 40 and 60 mg/l. Metoprolol did not affect gut motility. Metoprolol was similarly absorbed in the jejunum and ileum. The absorption rates appeared to be linearly related to the perfusion rates and to the mean concentration in the segment, indicating a first-order kinetic process. The absorption rate of metoprolol perfused in the jejunum in a saline solution appeared to be lower than that observed after gastric administration of the drug incorporated in a meal. The findings in this and other studies in this series indicate that metoprolol is similarly absorbed throughout the small intestine.

Investigation of drug absorption from the gastrointestinal tract of man. III. Metoprolol in the colon.

The colonic absorption of metoprolol was indirectly evaluated by measuring drug appearance in plasma following intravenous, jejunal or colonic infusion in six healthy volunteers. Plasma concentrations of alpha-hydroxymetoprolol and urinary excretion of the main metabolites were also measured. Plasma profiles of metoprolol after colonic and jejunal perfusion were similar, and the relative bioavailabilities of the drug from these two regions of the gut were not significantly different. The concentrations of alpha-hydroxymetoprolol, the major metabolite in plasma, were similar after jejunal and colonic perfusion, but higher than those observed after intravenous administration. The percentage of the dose recovered in urine over 24 h as two metabolites was not significantly influenced by the route of administration.

Investigation of drug absorption from the gastrointestinal tract of man. IV. Influence of food and digestive secretions on metoprolol jejunal absorption.

The influence of nutrients and digestive secretions on the intestinal absorption and bioavailability of the beta-adrenoceptor antagonist, metoprolol, was investigated in an isolated segment of jejunum using an intestinal perfusion technique. Two solutions containing metoprolol, one with, and one without nutrients, were perfused into the jejunum with an occluding balloon inflated or deflated. Jejunal fluid, blood and urine samples were then collected for drug or metabolite estimation. In the segment studied, metoprolol absorption from the nutrient solution was four times that observed during perfusion of the saline solution. Bile salts did not enhance drug absorption. Both in the presence and absence of nutrients, a linear relationship was observed between the computed cumulative amount of drug absorbed from the gastrointestinal tract and the resulting plasma concentration at each sampling time, indicating that first-pass loss was not saturated. This result was also reflected in the similarity of the AUC:dose ratios, and in the lack of effect of nutrients on the metabolism of the drug.

Investigation of drug absorption from the gastrointestinal tract of man. V. Effect of the beta-adrenoceptor antagonist, metoprolol, on postprandial gastric function.

The role of the adrenergic system in normal gastric function was assessed in five healthy volunteers by measuring gastric secretion and emptying after a mixed meal containing a non-absorbable marker, [14C]-PEG 4000, with and without 100 mg of metoprolol, a beta 1-adrenoceptor antagonist. Intraduodenal perfusion of PEG 4000, and gastric and jejunal sampling was achieved by means of a gastrointestinal intubation technique. Gastric function was assessed from the degree of dilution of the duodenal marker. Analysis of acid content by titration allowed the gastric acid secretory rate to be determined. Gastric emptying of a meal over 4 h was similar with and without metoprolol, the time to 50% emptying being 100 min. In the presence of metoprolol, gastric acid content was significantly increased during the late postprandial period producing a corresponding increase in acid load delivered to the duodenum. beta 1-adrenoceptor blockade appears to prolong the gastric secretory response to food without altering gastric emptying.

Investigation of drug absorption from the gastrointestinal tract of man. I. Metoprolol in the stomach, duodenum and jejunum.

Gastrointestinal (GI) absorption of the beta-adrenoceptor blocker metoprolol was investigated in five healthy subjects by means of an intubation method, employing a triple-lumen tube introduced into the intestine, and a twin-lumen tube in the stomach. Metoprolol was introduced into the stomach with a homogenized meal containing a nonabsorbable marker, [14C]-PEG 4000, and another marker, PEG 4000, was perfused continuously into the duodenum just below the pylorus. Samples of GI contents were collected at regular intervals over 4 h in the stomach and at two different levels in the upper small intestine. Metoprolol was not absorbed from the stomach. Approximately 60% of the amount of drug emptied from the stomach was absorbed from the duodenum; about 50% of that leaving the duodenum was absorbed from the first part of the jejunum. The delivery process was the rate-limiting factor of metoprolol absorption in these segments of the gut. Plasma concentrations reflected drug loss from the lumen and were higher in subjects exhibiting faster gastric emptying and higher absorption rates in the duodenum and jejunum. The intubation technique appeared to be a suitable method for investigating drug absorption from the GI tract in man.

[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.

Pharmacokinetic comparison of cefroxadin (CGP 9000) and cephalexin by simultaneous administration to humans.

The pharmacokinetic parameters of cefroxadin and cephalexin were compared after simultaneous oral administration of the two cephalosporins to 21 subjects. The influence of the dose, the formulation, and food intake on these parameters was investigated. Both drugs were equally well absorbed from all of the tested formulations; identical percentages of the dose were recovered in the urine in all cases. The elimination half-life of cefroxadin and, consequently, the area under the plasma concentration-time curve were about 10% less than those of cephalexin. Plasma concentrations and cumulative excretion curves of the two drugs were almost superimposable. Food intake had the same effect on both drugs; absorption was slowed, but the amounts absorbed were almost the same as those in fasted subjects.

Clinical pharmacology studies with acenocoumarol.

In two different studies, the relation between plasma concentrations of acenocoumarol and apparent prothrombin levels (Quick test) was investigated, using a new specific analytical method for the assay of the drug. The prothrombin level appeared independent of the plasma concentration of the drug, which is higher in old patients (over 70 years) than in younger patients (under 51 years).