Iron-loaded PLLA nanoparticles as highly efficient intracellular markers for visualization of mesenchymal stromal cells by MRI.

Monitoring of the fate of cells after injection appears paramount for the further development of cell therapies. In this context magnetic resonance imaging (MRI) is increasing in relevance owing to its unique tissue visualization properties. For assessment of cell trafficking and homing, the cells have to be labeled to become MR visible. The rather low sensitivity of MRI demands dedicated intracellular markers with high payloads of MR contrast agents for ensuring sensitive detection of local cell aggregations. In the presented work the application of custom-designed nanometer-sized iron oxide loaded poly-(l-lactide) (iPLLA) nanoparticles was investigated. The particles were synthesized by the mini-emulsion process and evaluated for labeling of mesenchymal stromal cells (MSCs). The efficient cellular uptake and long intracellular retention times of the particles as well as their nontoxicity are demonstrated. The average cellular iron content was 55 pg iron per cell. Further incorporation of, for example, fluorescent dye enables the generation of multireporter particles, providing the great potential for multimodal imaging. The efficiency of these nanoparticles as MRI contrast agent was evaluated in vitro using relaxation rate mapping, yielding relaxivities r2 = 273.3, r2 (*) = 545.1 mm(-1) s(-1) at 3 T and r2 = 415.7, r2 (*) = 872.3 mm(-1) s(-1) at 11.7 T. The high r2 (*) relaxivity of the iPLLA nanoparticles enabled visualization of a single labeled cell in vitro at 50-µm spatial resolution. In vivo evaluation in a rat injury model revealed the potential of the iPLLA particles to efficiently label MSCs for MRI monitoring of ~20 000-40 000 injected cells at 11.7 T. In conclusion the presented work demonstrates the applicability of iPLLA particles as efficient intracellular marker for MSC labeling for monitoring the fate of the cells by MRI.

Effect of the lipase inhibitor orlistat on the pharmacokinetics of four different antihypertensive drugs in healthy volunteers.

OBJECTIVE: To study the influence of the lipase inhibitor orlistat on the pharmacokinetics of the antihypertensive drugs atenolol, furosemide, captopril and nifedipine. METHODS: Four open-label, crossover studies were performed on six to eight healthy male volunteers. Orlistat was given in doses of 50 mg 3 times daily mid-meal for 7 (nifedipine and captopril) or 8 days (atenolol and furosemide). The four antihypertensive drugs (atenolol 100-mg tablet, furosemide 40-mg tablet, captopril 50-mg tablet and nifedipine 20-mg slow-release tablet) were administered in single doses twice, once before and once together, with orlistat at the end of the orlistat treatment period. RESULTS: The plasma concentration time profiles and the pharmacokinetic parameters estimated for these drugs were in the expected range, except for furosemide, whose bioavailability was lower than reported in the literature. This was probably due to the fact that furosemide was given during a meal. There were minor, but statistically significant, differences in one of the pharmacokinetic parameters of furosemide and nifedipine (no difference for captopril and atenolol) when these drugs were given alone and in combination with orlistat: the half-life of furosemide was slightly longer, the time to peak plasma concentrations of nifedipine was slightly longer. None of these are considered to be clinically significant changes. CONCLUSIONS: The lipase inhibitor orlistat given 50 mg 3 times daily does not alter the pharmacokinetics of atenolol, furosemide, nifedipine and captopril to a clinically significant extent.

[Early evening administration of ranitidine in therapy of duodenal ulcer]. / Die frühabendliche Einnahme von Ranitidin in der Therapie des Ulcus duodeni.

In this randomized clinical study the effect of 300 mg ranitidine given either after an early evening meal (abt. 6 p.m.) (n = 136) or at bedtime (abt. 10 p.m.) (n = 145) was investigated in 279 patients with an acute duodenal ulcer (79 women, 200 men, age median 40 years). To provide a double blind design, patients of each therapy group were given a placebo tablet either at 10 p.m. or at 6 p.m. (double dummy technique). After 2 and 4 weeks of therapy, the healing rates for the early resp. late evening doses were 75.6% and 65.9% (p = 0.054) and 95.5% and 94.2%, respectively. The healing rates for patients with an ulcer diameter between 5 mm and 9.5 mm and with a case history of duodenal ulcer, however, were significantly higher for the early evening doses of 300 mg ranitidine (85 vs. 65%, p less than 0.01, and 75 vs. 60%, p less than 0.05). The study results indicate that an early (abt. 6 p.m.) as well as a late (abt. 10 p.m.) evening doses of 300 mg ranitidine have a comparable positive effect on the healing of an acute duodenal ulcer, with the early evening doses having advantages in special patient groups.