Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume.

PURPOSE: CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-beta). Studies in animals have suggested that PDGFR-beta inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies. PATIENTS AND METHODS: Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters. RESULTS: Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P < .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels. CONCLUSION: These observations suggest that inhibition of PDGFR-beta might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.

Patterns of diversity in plant and soil microbial communities along a productivity gradient in a Michigan old-field.

The relationship between plant diversity and productivity has received much attention in ecology, but the relationship of these factors to soil microbial communities has been little explored. The carbon resources that support soil microbial communities are primarily derived from plants, so it is likely that the soil microbial community should respond to changes in plant diversity or productivity, particularly if the plant community affects the quality or quantity of available carbon. We investigated the relationship of plant diversity and productivity to the composition of the soil microbial community along a topographic gradient in a mid-successional old-field in southwestern Michigan. Soil moisture, soil inorganic N, and plant biomass increased from the top to the base of the slope, while light at ground level decreased along this same gradient. We characterized the changes in resource levels along this gradient using an index of productivity that incorporated light levels, soil N, soil moisture, and plant biomass. Average plant species richness declined with this productivity index and there were associated compositional changes in the plant community along the gradient. The plant community shifted from predominantly low-growing perennial forbs at low productivities to perennial grasses at higher productivities. Although there was variation in the structure of the soil microbial community [as indicated by fatty acid methyl ester (FAME) profiles], changes in the composition of the soil microbial community were not correlated with plant productivity or diversity. However, microbial activity [as indicated by Biolog average well color development and substrate-induced respiration (SIR)] was positively correlated with plant productivity. The similarity between patterns of plant biomass and soil microbial activity suggests that either plant productivity is driving microbial productivity or that limiting resources for each of these two communities co-vary.

The treatment of childhood nocturnal enuresis in the community.

The nature of childhood nocturnal enuresis and its psychological treatment are briefly reviewed and the major features relevant to providing a community service are identified. A treatment system is outlined, based on criteria for inclusion, particular treatment packages, specifiable number of contacts and predetermined definitions of success. The operation of this treatment system by a small multidisciplinary team in a community clinic setting is described and data to demonstrate the running and efficacy of the service are presented.

Decreased systemic clearance of caffeine due to cimetidine.

1 Five normal subjects received pre-treatment with cimetidine 200 mg three times daily and 400 mg at night for 6 days, or matching placebo. 2 Caffeine (300 mg) was given orally before any treatment and at the beginning of the last day of each treatment course. Treatments were randomly allocated and separated by at least one week. 3 A significant reduction occurred in the systemic clearance of caffeine and the half-life was prolonged as determined from measurement of caffeine in plasma and saliva. No change occurred in the apparent volume of distribution. 4 The oral bioavailability of caffeine was found to be complete in the one subject studied. 5 It is suggested that cimetidine inhibits the microsomal metabolism of caffeine. Although the steady state plasma caffeine would increase by approximately 70%, it is unlikely that this would produce adverse clinical effects.

Plasma and salivary pharmacokinetics of caffeine in man.

Plasma and salivary caffeine concentrations were measured by gas-liquid chromatography in 6 healthy caffeine-free volunteers following oral administration of 50, 300, 500 and 750 mg caffeine. Caffeine was also given to a single subject intravenously in doses of 300, 500 and 750 mg. Caffeine was rapidly absorbed and was completely available at all doses. The apparent first-order elimination rate constant decreased linearly with dose and was 0.163 +/- 0.081 h-1 for 50 mg and 0.098 +/- 0.027 h-1 for 750 mg. The total body clearance was unaffected by dose and was 0.98 +/- 0.38 ml/min/kg. There was a trend towards increasing apparent volume of distribution with increasing dose. A linear relationship existed between the area under the plasma concentration, time curve and dose and dose-normalised plasma concentration, time plots were superimposable. These findings suggest that caffeine obeys linear pharmacokinetics over the dose range investigated. Despite significant inter-individual differences in pharmacokinetic parameters there was good reproducibility within 5 subjects given 300 mg caffeine orally on 3 occasions. Salivary caffeine levels probably reflect the unbound plasma caffeine concentration and can be used to estimate the pharmacokinetic parameters of the drug. Overall the saliva/plasma concentration ratio was 0.74 +/- 0.08 but within subjects some time-dependence of the ratio was found with higher ratios initially (even after intravenous administration) and lower ratios at longer time intervals after the dose. Urinary elimination of caffeine was low and independent of dose: 1.83% of the dose was eliminated unchanged.