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Notes: This three-way randomized crossover study in 18 healthy male volunteers compared the pharmacokinetics of 50 mg indomethacin b.d. during concomitant twice daily dosing with 400 μg misoprostol, 150 mg ranitidine or placebo. Plasma indomethacin concentrations were determined by HPLC assay of samples collected over 12 h after the first dose, and over 14 h after the last dose on Day 8 of each dosing period. A daily diary of bowel habits, and the occurrence and severity of abdominal symptoms, was kept by each subject throughout the study. Statistical comparisons were made by analysis of variance.In the presence of misoprostol there was a 13% decrease in the area under the plasma concentration-time curve of indomethacin over one dosing interval on Day 1 (P 〈 0.01), and at steady state there was a 24% decrease in the maximum plasma concentration (P 〈 0.02). The pharmacokinetics of indomethacin were not affected by co-administration of ranitidine. Accumulation of indomethacin after repeated oral dosing was not significantly altered by the co-administration of either misoprostol or ranitidine. The frequency and severity of abdominal symptoms was significantly increased (P 〈 0.01) during misoprostol dosing, compared with either ranitidine or placebo plus indomethacin. When the dosing phase (Days 1–8) was compared with the washout phase (Days 9–15) in each period, misoprostol, but not ranitidine or placebo, plus indomethacin resulted in an increase (P 〈 0.001) in abdominal symptom severity, frequency of bowel motions and a decrease in faecal consistency.

Notes: Omeprazole is a racemate, from which the R- and S-isomers can be isolated. At the cellular level, both of these isomers convert to the same inhibitor of the H+,K+-ATPase and produce the same reduction in gastric acid secretion. However, the S-isomer, esomeprazole, is metabolized more slowly and reproducibly than the R-isomer and omeprazole, and therefore produces higher plasma concentrations for longer and, as a result, inhibits gastric acid production more effectively and for longer. Thus, esomeprazole has the pharmacological properties of a more effective form of treatment for disorders related to gastric acid secretion. Clinical studies have confirmed the anticipated increased efficacy, but have shown no evidence of impaired tolerability or increased toxicity when compared with omeprazole.

Notes: The impact of cimetidine, ranitidine and placebo on the pharmacokinetics of metoprolol, given either as a single dose (100 mg) or for 7 days (100 mg b.d.), has been evaluated in two separate studies. The doses used were 800 mg cimetidine daily and 300 mg ranitidine daily. The subjects were all young, healthy volunteers. In the single dose study, cimetidine produced a marked increase in the peak plasma concentration of metoprolol and in the area under the plasma concentration-time curve; ranitidine had less effect, though the area under the curve was significantly greater than placebo. In the chronic dosing study, the area under the curve for metoprolol was also significantly higher on cimetidine (1796 ng h/ml; P 〈 0.001) whereas the area under the curve on ranitidine (1258 ng h/ml) was comparable to that on placebo (1183 ng h/ml). Despite these drug-induced changes in plasma metoprolol concentration, neither cimetidine nor ranitidine altered the change in exercise-induced heart rate during dosing with metoprolol.

Notes: We consider the shear-wave polarization vectors and rays as a wavefront passes from an isotropic region into one where the anisotropy increases gradually from zero. This is a necessary first step when analysing the solution of the wave equation in such a transition. The method involves an idealized situation where there is a jump in, say, the third derivative of the elastic parameters along the border between the isotropic and anisotropic regions. Velocity and slowness on the incident rays are then continuous with those on the splitting rays in the anisotropic region. Higher derivatives of velocity and slowness are discontinuous, however, and these jumps are found. The first derivative of polarization wrt time along rays is generally discontinuous, although its component in the ray direction itself is conserved. This discontinuity in the rate of change of polarization is used to demonstrate how, or why, the usual asymptotic ray method fails to satisfy the wave equation in such a transition region. The results are used in a companion paper on the transition zone problem and the methods should be useful in other problems where shear wavespeeds coalesce and the geometry of the rays controls the resulting interference.

Notes: Our recent observations in man suggested that the secretion of the thymic peptide, thymulin, is influenced by hormones of the pituitary-adrenal axis. In the present study, we have used the rat as a model in order to examine 1) the effects of corticotrophin (ACTH) and glucocorticoids on the release of thymulin in vivo and in vitro, and 2) the influence of an acute rise in plasma thymulin on the secretion of corticosterone and luteinizing hormone.Immunoreactive thymulin was readily detectable in plasma from male Sprague-Dawley rats(≃200 g). Chronic bilateral adrenalec-tomy, which effectively removed endogenous corticosterone, produced highly significant (P〈0.01) increases in the plasma concentrations of both ACTH and thymulin. Treatment of the adrenalectomized rats with dexamethasone, in a dose sufficient to suppress the hypersecretion of ACTH, maintained the plasma thymulin at a low level which did not differ significantly (P 〉 0.2) from that in sham-operated controls.In vitro, two non-specific depolarizing agents, K+ (56 mM) and veratridine (10 ≃M), caused significant (P〈0.01) Ca2+-dependent increases in thymulin release from segments of rat thymic tissue. Their effects were mimicked by ACTH1–39. The secretory responses to ACTH (0.025 to 1 ng/ml) were concentration-dependent but a very high concentration (2 ng/ml) of the peptide was without effect. Dexamethasone (0.1 μM) reduced (P〈0.05) the spontaneous release of thymulin in vitro but potentiated markedly (P〈0.01) the secretory responses to ACTH (0.5 to 1.0 ng/ml).Administration of thymulin (0.1 and 10 μg/kg ip) produced, within 10 min, striking increases in the plasma thymulin concentration which were still evident at 30 min. The peptide concentration then declined rapidly and, within 24 h, was lower than that in the corresponding vehicle-treated controls. The serum concentrations of corticosterone and luteinizing hormone were unaffected by the thymulin treatment. The saline vehicle (2.0 ml/kg ip) also produced a small increase in plasma thymulin concentration which was maximal at 10 min; a further small rise was evident 6 h after the injection but thereafter the thymulin values were indistinguishable from those in uninjected controls. A similar biphasic profile of serum corticosterone was apparent after the saline injection but the serum luteinizing hormone was unaffected.The results suggest that ACTH is a physiological enhancer of thymulin release and that, in certain circumstances, its effects may be potentiated by glucocorticoids.

Notes: Abstract Samples of the macrobenthic fauna of soft sediments were collected from around Svalbard during the 1991 Arctic EPOS cruise of RVPolarstern. Although faunal variability could be related to sediment granulometry and depth, all stations to the south and east of the Archipelago lay within the broadly defined central Barents Sea community. In this community,α-diversity was variable and sampled between 77 and 337 m showed no clear relationship to depth. Diversity in the area close to the polar front was notably high, rarefaction predicting that 43±5.5 species might occur in a sample of 201 individuals.k-Dominance plots suggested that muddy sand communities around Svalbard were no less diverse than similar assemblages in the North Sea.