Herbivory on marine macroalgae (seaweeds) in temperate areas is often dominated by relatively small gastropods and crustaceans (mesoherbivores). The effects of these herbivores on the performance of adult seaweeds have so far been almost exclusively investigated under artificial laboratory conditions. Furthermore, several recent laboratory studies with mesoherbivores indicate that inducible chemical resistance may be as common in seaweeds as in vascular plants. However, in order to further explore and test the possible ecological significance of induced chemical resistance in temperate seaweeds, data are needed that address this issue in natural populations. We investigated the effect of grazing by littorinid herbivorous snails (Littorina spp.) on the individual net growth of the brown seaweed Ascophyllum nodosum in natural field populations. Furthermore, the capacity for induced resistance in the seaweeds was assessed by removing herbivores and assaying for relaxation of defences. We found that ambient densities of gastropod herbivores significantly reduced net growth by 45% in natural field populations of A. nodosum. Seaweeds previously exposed to grazing in the field were less consumed by gastropod herbivores in feeding bioassays. Furthermore, the concentration of phlorotannins (polyphenolics), which have been shown to deter gastropod herbivores, was higher in the seaweeds that were exposed to gastropod herbivores in the field. This field study corroborates earlier laboratory experiments and demonstrates that it is important to make sure that the lack of experimental field data on marine mesoherbivory does not lead to rash conclusions about the lack of significant effects of these herbivores on seaweed performance. The results strongly suggest that gastropods exert a significant selection pressure on the evolution of defensive traits in the seaweeds, and that brown seaweeds can respond to attacks by natural densities of these herbivores through increased chemical resistance to further grazing.

Aims The main purpose of this paper is to describe the relationship between serum concentrations of glibenclamide and its main metabolites and the effects on blood glucose levels, the clinically most relevant parameter to assess in diabetes. Methods Serum concentrations and blood glucose lowering effects (expressed as percent blood glucose reduction vs placebo) of glibenclamide (Gb) and its active metabolites, 4-trans-hydroxy-(M1) and 3-cis-hydroxy-glibenclamide (M2), were analysed in eight healthy subjects participating in a placebo-controlled, randomized, single-blind crossover study, using intravenous administration of each compound as well as oral administration of Gb. Results Plots of % blood glucose reduction vs log serum concentration demonstrated counter-clockwise hysteresis for parent drug and its metabolites. An effect compartment was linked to appropriate pharmacokinetic models and pharmacokinetic and pharmacodynamic modelling was used to fit the pharmacokinetics of Gb by both routes and the metabolites for each individual. Based on the individual concentration-time profiles a PK/PD-model was applied to all effect data simultaneously. An increase in the steady-state serum concentration when the effect is 50% of maximal, CE ss50, , was found in the sequence M1 (23 ng ml −1 ), M2 (37 ng ml −1 ) and Gb (108 ng ml −1 ). Corresponding interindividual variabilities expressed as CV% were 25%, 47% and 26%. The elimination rate constants from the effect site (k E0 ) were estimated and increased in the order M1 (0.178 h −1 , CV 13%), M2 (0.479 h −1 , CV 8.5%) and Gb (1.59 h −1 , CV 36%). Corresponding equilibration half-lives for the effect site (k E0-HL ) were 3.9 h, 1.4 h and 0.44 h. Estimated E max -values obtained for M1, M2 and Gb were 40% (CV 30%), 27% (CV 56%) and 56% (CV 14%), respectively. Conclusions It is concluded that the two major metabolites of Gb are hypoglycaemic in man, that they may have higher activity at low concentrations and that they may have a longer effect duration than the parent drug.

These abstracts have been accepted for publication by the Dutch Society of Clinical Pharmacology and BiopharmacyNihon Kohden® and Cambridge Electronic Design (CED®) hardware and Spike2® software at 1 : 35 post drug administration. Results were statistically evaluated using GLM in SPSS® 11.5. Results:Results are presented in table 1. Saccadic peak velocity was increased after MDMA (p = 0.000). Co-administration showed significant increase in peak saccadic velocity compared to placebo (p = 0.004), although significantly less then the increase as observed after MDMA alone (p = 0.003). Smooth pursuit was significantly impaired after ethanol compared to placebo (p = 0.000) and MDMA (p = 0.000), co-adminstration also impaired score compared to placebo (p = 0.000) and MDMA (p = 0.000).Conclusions: MDMA induced arousal as measured by the saccadic peak velocity when administered alone and, to a lesser degree, in combination with ethanol. Co-administration of MDMA with ethanol however could not ameliorate the deterioration of psychomotor accuracy by ethanol as measured by smooth pursuit eye movements. These findings suggest that although MDMA might ameliorate ethanol induced sedation it does not ameliorate impaired psychomotor skills. This might give a false sense of improved performance while intoxicated and thus increases risks of for example road accidents. Introduction: A considerable percentage of young people expose themselves to 3,4-methylenedioxy-methamphetamine (MDMA or 'ecstasy'). Alcohol is relatively commonly used in combination with MDMA (Barrett et al., 2005). As a percentage of MDMA users admit to driving under influence (Riley et al., 2001), the assessment of the effects of co-administration of these substances on psychomotor performance is warranted. Hypothesis:We hypothesized that the co-administration of MDMA and ethanol would ameliorate the impairment induced by ethanol alone. Methods:We performed a double-blind, randomized, placebocontrolled study in 16 healthy volunteers (9 male, 7 female) in the age of 18-29 years. MDMA 100 mg was given orally and blood alcohol concentration (BAC) was maintained at 0.6‰ by a three hour 10% alcohol infusion regime (adjustment of infusion rate according to regular sampled breath alcohol concentration). Saccadic and smooth pursuit eye movements, a validated measure of ethanol induced sedation (van Steveninck et al., 1999), were recorded using Objectives: This study firstly aimed to identify the percentage of nursing home patients who were prescribed more than nine drugs (polypharmacy) and compared prescribing patterns of this patient group to patients who were prescribed fewer drugs. Secondly, teams of hospital pharmacists and nursing home physicians aimed to identify the drug related problems of the polypharmacy patients and the extent to which it was feasible to optimise their medication profiles.Methods: Characteristics of the polypharmacy population were illustrated by retrospective point measurements in five Dutch nursing homes (total of 742 beds) over the years ...

PURPOSE COL‐3, a matrix metalloproteinase inhibitor, has been evaluated in phase I/II clinical trials for the treatment of cancer. The objective was to establish a population pharmacokinetic (PK) model of COL‐3 in cancer patients. METHODS 740 COL‐3 plasma concentration data were obtained from 34 cancer patients in a single‐dose, dose‐escalation (from 36 to 98 mg/m2/day) phase I study. Intense PK sampling was obtained after the first dose and trough concentrations were obtained throughout the treatment. A population PK model of COL‐3 was developed with first‐order conditional estimation using NONMEM. RESULTS A one‐compartment model with sequential zero‐order input, mimicking dissolution, and first‐order absorption and elimination described plasma concentration‐time profiles well. Estimated population means (RSE%) for apparent clearance and mean absorption time were 0.78 (6%) L/h and 1.8 (7%) h, with interindividual variability of 57% (40%) and 41% (27%), respectively. Covariate screening indicated that V/F was dose‐dependent, while body weight, body surface area, sex, age, and creatinine clearance did not exhibit any significant impact on COL‐3 PK. CONCLUSIONS A linear one‐compartment model with sequential zero‐ and first‐order absorption adequately describes COL‐3 PK in cancer patients. This population PK model supports fixed‐dosing of COL‐3. The dose‐dependence of Vd/F is likely the result of reduction in bioavailability (F) with increasing dose due to poor dissolution. Clinical Pharmacology & Therapeutics (2005) 79, P20–P20; doi: