Timing of food intake has a marked effect on the bioavailability of clodronate.

Because of the low and variable bioavailability of bisphosphonates and the huge effect of food on their gastrointestinal absorption, it is of utmost importance to know the optimal timing of drug intake in relation to food intake. We investigated the effect of time on the bioavailability of clodronate when the drug was administered 2, 1, or 0.5 h before breakfast, with breakfast, or 2 h after breakfast (in the middle of a 4-h fast). The study was conducted as a single-center, open, balanced, randomized, crossover pharmacokinetic study in 31 healthy subjects aged 21 to 34 years. The volunteers participated in five different sessions with 800 mg of oral clodronate, and these sessions were separated by washout phases, each for at least 1 week. The primary pharmacokinetic variables were the area under the serum concentration time curve in 24 h (AUC(0-24)) for clodronate and the maximal concentration of clodronate in serum (C(max)). Clodronate was absorbed rather similarly when taken in the morning on an empty stomach 2, 1, or 0.5 h before breakfast, but because the best absorption occurred (as expected) when the drug was taken 2 h before breakfast, this scheme served as the reference treatment. As evaluated by area under the serum concentration time curves, the dose-breakfast interval of 1 h scarcely reduced absorption from the reference treatment level (relative absorption 91%, p = 1.0). Compared with the reference treatment, clodronate was absorbed with 69% efficacy (p = 0.65) when breakfast followed only 0.5 h later. The dose-breakfast intervals of 0.5 and 1 h did not differ significantly from each other (p = 0.85). Absorption was, however, only 34% (p < 0.0001) of the optimum when the drug was taken 2 h after breakfast, and only 10% of optimal when clodronate was taken with breakfast (p < 0.0001). In conclusion, it can be recommended to take Bonefos capsules in the morning on an empty stomach at least 0.5 h before breakfast.

Bacteriophage T4 resistant mutants of the plant pathogen Erwinia carotovora.

Bacterial lipopolysaccharide (LPS) has been implied in a variety of pathogenic and symbiotic plant-bacterium interactions. In order to study the role of LPS in pathogenicity of Erwinia carotovora, a broad host range phytopathogen, we isolated LPS defective mutants of two subspecies of Erwinia carotovora, subsp. carotovora (Ecc) and subsp. astroseptica (Eca). This was accomplished by using the Escherichia coli phage T4 as a selective agent. Screening of Erwinia isolates revealed that some of them were sensitive to T4 and thus T4 could be employed in mutant isolation. Fully T4 resistant mutants were all shown to be defective in their LPS structure. Preliminary pathogenicity tests on tobacco did not, however, reveal any decrease in the virulence of the LPS defective strains.