Volcanic evolution of an ultraslow-spreading ridge.

Nearly 30% of ocean crust forms at mid-ocean ridges where the spreading rate is less than 20 mm per year. According to the seafloor spreading paradigm, oceanic crust forms along a narrow axial zone and is transported away from the rift valley. However, because quantitative age data of volcanic eruptions are lacking, constructing geological models for the evolution of ultraslow-spreading crust remains a challenge. In this contribution, we use sediment thicknesses acquired from ~4000 km of sub-bottom profiler data combined with 14C ages from sediment cores to determine the age of the ocean floor of the oblique ultraslow-spreading Mohns Ridge to reveal a systematic pattern of young volcanism outside axial volcanic ridges. Here, we present an age map of the upper lava flows within the rift valley of a mid-ocean ridge and find that nearly half of the rift valley floor has been rejuvenated by volcanic activity during the last 25 Kyr.

Identification of peptides from foot-and-mouth disease virus structural proteins bound by class I swine leukocyte antigen (SLA) alleles, SLA-1*0401 and SLA-2*0401.

Characterization of the peptide-binding specificity of swine leukocyte antigen (SLA) class I and II molecules is critical to the understanding of adaptive immune responses of swine toward infectious pathogens. Here, we describe the complete binding motif of the SLA-2*0401 molecule based on a positional scanning combinatorial peptide library approach. By combining this binding motif with data achieved by applying the NetMHCpan peptide prediction algorithm to both SLA-1*0401 and SLA-2*0401, we identified high-affinity binding peptides. A total of 727 different 9mer and 726 different 10mer peptides within the structural proteins of foot-and-mouth disease virus (FMDV), strain A24 were analyzed as candidate T-cell epitopes. Peptides predicted by the NetMHCpan were tested in ELISA for binding to the SLA-1*0401 and SLA-2*0401 major histocompatibility complex class I proteins. Four of the 10 predicted FMDV peptides bound to SLA-2*0401, whereas five of the nine predicted FMDV peptides bound to SLA-1*0401. These methods provide the characterization of T-cell epitopes in response to pathogens in more detail. The development of such approaches to analyze vaccine performance will contribute to a more accelerated improvement of livestock vaccines by virtue of identifying and focusing analysis on bona fide T-cell epitopes.

Stereoselective pharmacokinetics of disopyramide and interaction with cimetidine.

The pharmacokinetics of each of the enantiomers of disopyramide were examined after i.v. bolus administration of 150 mg racemic drug in a randomized cross-over study before and after the administration of cimetidine 400 mg twice daily orally. Clearance and volume of distribution (Vz) of total drug were significantly (P less than 0.001) higher for the R-(-) enantiomer than the S-(+) enantiomer (7.9 vs 4.6 l h-1 and 89 vs 50 l, respectively), whereas no significant difference in half-life could be demonstrated. The clearance of free drug was significantly (P less than 0.05) higher for the S-(+) enantiomer than that of the R-(-) enantiomer (34.6 +/- 5.4 l h-1 vs 27.2 +/- 5.6 l h-1), whereas no significant enantioselective difference in unbound volumes of distribution (258 +/- 38 l vs 226 +/- 42 l) could be demonstrated. Coadministration of cimetidine did not alter the pharmacokinetics of disopyramide. A significant concentration- or time-related decrease in the renal clearance of each of the enantiomers measured with respect to total drug in serum was observed, whereas renal clearances of the free enantiomers were similar.

Disposition kinetics of disopyramide in human healthy volunteers described by an open three compartment model.

Disposition kinetics of disopyramide was examined in an open randomised cross-over study in 8 healthy volunteers. Disopyramide was randomly administered as a single bolus injection (150 mg) over a period of 5 min. and as an infusion (28.2) mg/h to steady state. Disposition kinetics of disopyramide were most precisely described by an open three compartment model according to Akaike's information criteria. Significant positive correlations (0.909 +/- 0.04, P less than 0.05 (injection study); 0.787 +/- 0.11, P less than 0.05 (infusion study] were observed between total serum concentrations of disopyramide and renal clearance while no significant correlation could be demonstrated between free serum concentrations and renal clearance. This implies a constant value of unbound renal clearance. The results are consistent with non linear kinetics (mainly caused by the variable free fraction of the drug), when based on total serum concentrations. The disposition of unbound disopyramide, however seems to be linear (i.e. the kinetic parameters are independent of dose) in the bolus injection study. Total elimination clearance (free and total), volume of distribution and elimination half-life were significantly higher in the steady state experiment than in the bolus injection study.

Elimination kinetics and urinary excretion of disopyramide in human healthy volunteers.

Elimination kinetics and the renal handling of disopyramide was examined in 8 healthy volunteers. Approximately 50% of the administered disopyramide undergoes hepatic metabolism (metabolic clearance = 116.1 +/- 42.2 ml/min.), while the rest is excreted by the kidneys (renal clearance = 101.9 +/- 21.6 ml/min.). Total renal excretion rate of disopyramide was 0.676 +/- 0.188 mumol/min. and 0.258 +/- 0.029 mumol/min. was excreted by glomerular filtration leaving a net tubular secretion of 60% of the total renal elimination. A significant positive correlation was observed between total serum concentrations and renal clearance values of disopyramide while no significant correlation could be obtained between serum concentrations of the unbound drug and renal clearance values of disopyramide, implying a constant value of unbound renal clearance. Hepatic blood flow was significantly (P less than 0.005) decreased following disopyramide infusion.

Haemodynamic effects of disopyramide using a new model of intravenous administration.

Intravenous treatment with disopyramide is usually performed by administration of a bolus injection of 150 mg given over 5 min. followed by a continuous infusion of 18-24 mg hour-1. A decrease in cardiac output is associated with this rapid bolus injection. Seven patients with ischaemic heart disease entered an open randomised cross-over trial to elucidate if an extension of the bolus injection time to 20 min. resulted in a smaller decrease in cardiac output. Cardiac index decreased significantly (P less than 0.001) in both situations, with maximum decrease observed at time 5 and 20 min., respectively (equivalent to the ending of the administration of 150 mg disopyramide). The decrease in Cardiac index (mean +/- S.E.M.) was identical in the two situations (2.56 +/- 0.23 to 1.78 +/- 0.21 l/min. X m2 (30%) and 2.66 +/- 0.17 to 1.94 +/- 0.19 l/min. X m2 (27%], respectively. Blood pressure was unchanged, while heart-rate (P less than 0.025) and preejection period index (P less than 0.005) increased significantly and to the same extent in the two situations. Significant correlations between the log free and log total serum concentration of disopyramide and the relative change in preejection period index of r = 0.840 (P less than 0.01) and 0.919 (P less than 0.01), respectively, were observed giving disopyramide over 5 min. A significant anticlockwise hysteresis was observed extending the time of administration to 20 min. As no haemodynamic advantages are achieved by the slower way of administration we would still recommend the bolus injection to be given over 5 min.

Displacement of lidocaine from human plasma proteins by disopyramide.

Displacement from human plasma proteins of lidocaine by disopyramide was investigated in serum from nine patients receiving lidocaine treatment because of severe ventricular arrhythmias. From each patient disopyramide in concentrations of 5.9 and 14.7 mumol/l was added to three different serum concentrations of lidocaine and the displacement was examined. At a serum concentration of disopyramide of 14.7 mumol/l the percentage of unbound lidocaine increased from 30.4 +/- 0.2 to 36.3 +/- 0.2% (mean +/- S.E.M., P less than 0.001) at an average total serum concentration of lidocaine of 22.7 mumol/l. The study implies a stronger binding affinity of disopyramide than lidocaine to alpha-1-acid glycoprotein. We recommend caution when using disopyramide immediately after an infusion of lidocaine. With the dosage regimen used serum concentrations considerably above the suggested therapeutic level were achieved in the majority of patients.

Quantitative and qualitative binding characteristics of disopyramide in serum from patients with decreased renal and hepatic function.

Protein binding of disopyramide, binding capacities, affinity constants and serum concentrations of alpha 1-acid glycoprotein (AAG) were studied in five groups of patients. A: young healthy volunteers (n = 8); B: elderly patients with minor symptoms of ischaemic heart disease (n = 9); C: patients with cirrhosis of the liver and normal values of coagulation factors (II, VII and X), albumin and immunoglobulin G (n = 8); D: patients with cirrhosis and at least two abnormal of the previously mentioned values (n = 9) and E: eleven patients with severely impaired renal function. Subfractions of AAG (Fr1, Fr2 and Fr3) were determined by affinoimmunoelectrophoresis. AAG concentration was significantly (P less than 0.005) elevated in group E patients and decreased (P less than 0.025) in group D patients. Fr2 is probably associated with the high affinity, first binding site of disopyramide to AAG. Earlier observations of a reduced qualitative binding of disopyramide in patients with cirrhosis can be explained by a significant decrease in Fr2 (P less than 0.001) in group D patients. The protein binding of disopyramide in patients with uraemia was significantly increased due to a significant (P less than 0.005) increase in AAG concentration in spite of a smaller (P less than 0.025) affinity constant. Suggestions for therapeutic drug monitoring based on total serum concentrations are given.

The analgesic effect of buprenorphine, etorphine and pethidine in the pig: a randomized double blind cross-over study.

In order to find a suitable analgesic for the treatment of postoperative pain in pigs the analgesic effect of buprenorphine, etorphine and pethidine has been compared in 8 domestic pigs. For assessment of the analgesic action on thermal (hot plate) and two mechanical (cannulation of ear vein, needle prick) noxious stimuli have been employed. In a pilot experiment on 2 pigs in which methadone was included the maximal effective doses were estimated for each drug. Methadone was found unsuitable because of unacceptable side effects (respiratory dysfunction, hyperactivity) at effective dose levels. Next buprenorphine 120 micrograms/kg, etorphine 3 micrograms/kg and pethidine 20 mg/kg all given intramuscularly were compared in a randomized blind trial with a balanced cross-over design on 6 pigs. Etorphine proved to have the highest and pethidine the lowest maximal analgesic effect which was especially evident in the needle-prick test. Buprenorphine proved to have the longest duration of action in all three analgesic tests, in the hot plate test lasting between 7 and 24 hrs. Etorphine had a duration of 3 to 5 hrs whereas the effect of pethidine was short, only lasting about 2 hrs. Etorphine provides a complete analgesia but has a small safety margin for which reason it should be used with caution in the pig. The experimental results indicate that buprenorphine should be the first drug of choice in the treatment of pain after surgical intervention due to its long duration of action and lack of side effects.

The pharmacokinetics and protein binding of disopyramide in pigs.

The pharmacokinetics of disopyramide were investigated in 5 pigs. Disopyramide was administered as intravenous bolus injections at different doses and as intravenous infusions at different rates. By measuring the free and total concentrations in plasma of parent compound and desisopropyldisopyramide (the main metabolite in humans) and the amounts excreted in urine it was found that disopyramide had a concentration dependent protein binding and that free and total concentrations could be described by a two-compartment model with a t1/2, beta of approximately 2 hours. The free concentrations were found to be more valuable for estimating the kinetic parameters. The total clearance of disopyramide in the pig was found to approximately 3 ml/min./kg which is about 3 times greater than in man. In contrast to humans the free clearance in the pig increased with declining concentration. Apart from this the kinetics of disopyramide in the pig were very similar to those in man. In conclusion the pig could be a relevant model for studying the pharmacokinetics in humans.

Kinetics of disopyramide in decreased hepatic function.

The elimination kinetics of disopyramide was studied in 9 patients with decreased hepatic function (DHF) due to histologically verified cirrhosis of the liver, and in 11 patients with ischaemic heart disease (IHD). Disopyramide 100 and 150 mg was given intravenously as a bolus to the patients with IHD and DHF, respectively, followed by a continuous infusion of disopyramide 0.3 (DHF group) and 0.4 mg X min-1 (IHD group) until steady-state was achieved. A significant (p less than 0.001) positive correlation between the percentage unbound and total serum concentration of disopyramide was demonstrated in both groups. The percentage of unbound disopyramide at a total serum concentration of 5.9 mumol X l-1 was 45.5% and 19.4% in the DHF and IHD groups, respectively. A negative correlation (r = -0,751, p less than 0.05, and r = -0.827, p less than 0.01 in the IHD and DHF patients, respectively) between the free fraction of disopyramide and alpha 1-acid glycoprotein was observed. The serum concentration of alpha 1-acid glycoprotein, the major binding protein of disopyramide, was significantly lower in the patients with DHF. The clearance of unbound disopyramide and its total volume of distribution and half-life were significantly lower in the DHF patients. No difference in total elimination clearance could be demonstrated. The clinical implication of the present findings appear to be that the dosage of disopyramide should be reduced by 25% when it is given intravenously to patients with decreased hepatic function.

Haemodynamic effects and kinetics of concomitant intravenous disopyramide and atenolol in patients with ischaemic heart disease.

The haemodynamic effects of concomitant intravenous administration of disopyramide (Norpace) and atenolol (Tenormin) were studied in a cross-over trial in 7 patients with ischaemic heart disease. Following 150 mg disopyramide i.v. the cardiac index (CI) and stroke volume index (SVI) decreased by 14% and 26%, respectively and the heart rate (HR) and preejection period index (PEPI) increased by 13% and 19%, respectively. A decrease in CI of 14% and HR of 21%, respectively were noted after intravenous administration of 7.5 mg atenolol; PEPI increased by 10% whereas SVI remained unchanged. The cardiac Index (CI) fell by 33% following the administration of both drugs. The effect on CI of the two drugs was additive. The effect of disopyramide and atenolol on HR, SVI and PEPI was not significantly modified by coadministration of the other drug. No change in blood pressure was observed after disopyramide or atenolol. A correlation (rho) of 0.540 and 0.387 was observed between the change in PEPI and the log free and total serum concentrations of disopyramide, respectively. Combined intravenous use of the two drugs in patients with incipient or overt heart failure is not recommended, unless it is due to the arrhythmia to be treated.

The influence of age and smoking on the elimination of disopyramide.

The influences of smoking and age on the elimination kinetics of disopyramide were studied in 27 subjects. Total elimination clearance of disopyramide was measured after an infusion to steady state. The total elimination clearance was significantly (P less than 0.05) decreased in elderly non-smoking patients compared with young non-smoking subjects (1.54 +/- 0.33 vs 2.12 +/- 0.67 ml kg-1 min-1) (mean +/- s.d.). Smoking more than 20 cigarettes per day significantly (P less than 0.05) increased total elimination clearance in elderly (2.02 +/- 0.35 vs 1.54 +/- 0.33 ml kg-1 min-1), while no significant induction by tobacco was observed in young healthy persons. Serum concentrations of alpha 1-acid glycoprotein, the major binding protein of disopyramide, were significantly higher (P less than 0.001) in the elderly patients. However, the volume of distribution (V) was significantly (P less than 0.001) greater in the elderly patients (2.44 +/- 0.64 vs 1.16 +/- 0.15 1 kg-1). Steady-state serum concentrations of the free drug were significantly (P less than 0.01) lower in the young volunteers (0.75 +/- 0.13 micrograms ml-1) than in the elderly (0.90 +/- 0.10 micrograms ml-1). The half-life of disopyramide was significantly shorter (P less than 0.01) in the young volunteers than in the elderly patients. No difference was observed in the relationship between the serum concentration of disopyramide and its main dealkylated metabolite in the groups studied. The results indicate that it might be advisable to reduce the dosage of disopyramide by approximately 30% in elderly non-smokers compared with young subjects.

The effect of charatoxin, 4-methylthio-1,2-dithiolane, on the frog sartorius neuromuscular junction.

The insecticide 4-methylthio-1,2-dithiolane, named charatoxin, blocks the frog muscular twitches elicited through the neuromuscular junction. The activity level and the course of inhibition is comparable to that of 4-dimethyl-amino-1,2-dithiolane, nereistoxin.