Over the years, the number of studies and quality of methodology has increased. The most frequently observed outcomes with a positive impact were appropriateness of prescribing and cost savings. The vast majority of studies used multiple interventions, in conjunction with pharmacists' recommendations to physicians. Coupled with the use of practice guidelines or educational strategies, these interventions demonstrated a positive impact on economic or clinical outcomes. However, the data are still sparse and sometimes contradictory; therefore, further studies with randomized controlled designs are needed.

The pharmacokinetics of Cyclosporin A (CyA, Sandimmune) was studied in 12 healthy male volunteers after oral dosing of 350 mg, 700 mg, and 1400 mg as a drinking solution. Blood samples were collected over 96 hr and analyzed by high pressure liquid chromatography. Concentration data were evaluated with model-independent and model-based linear pharmacokinetic concepts. Individual CyA concentration-time profiles in whole blood were well described by a two-compartment open model with zero-order absorption for all three doses. Comparison of pharmacokinetic parameters across doses indicates that both absorption and disposition are dose-dependent. Nonlinear disposition is suggested by the significant increase of the terminal half-life from 8.9 +/- 4.9 hr to 11.9 +/- 4.9 hr (mean +/- SD) after a 350 mg and a 1400 mg dose, respectively. Changes in the metabolic activity of the liver with concentration might be responsible for this phenomenon. In addition, the modeling approach indicated that bioavailability decreases with increasing dose. Moreover, the dependence of the rate of CyA absorption (zero-order rate constant) versus dose was well described by a hyperbola. The limited solubility of the drug in the gastrointestinal tract might be responsible for this behavior. The lag time (0.2-0.8 hr) was independent of dose. This value is similar to the time of gastric emptying in fasting volunteers. The duration of absorption for 11 of 12 subjects was in the range 2.5-3.5 hr over all doses and agrees well with the small intestine transit time. Some subjects showed a marked secondary peak at one or two doses, which could be adequately fitted by a model with two successive zero-order inputs. This double-peak behavior was ascribed to the influence of the food on gastric emptying. Dose dependency of disposition and absorption counterbalance each other in the usual dose range. This leads to an almost proportional increase of area under the blood CyA concentration-time profile with increasing dose.

Even though interdisciplinary interventions aiming at rationalizing antibiotic use could not diminish the duration of treatments, their costs or the length of stay, they proved useful to control the progression of these parameters.

No abstract

The influence of lipid vehicles on the intestinal absorption of Ciclosporin was studied in vitro. The effect of the intestinal lipid digestion was considered on the partition of the drug from olive oil or middle-chain triglyceride (MCT) into phases of simulated intestinal content. The phases obtained after ultracentrifugation were analyzed for their Ciclosporin content and characterized for their lipid classes. For both lipid vehicles the presence of lipolysis products did not promote the partition of the drug into the aqueous phase. The absorption in vivo was not related to the drug amount in the aqueous phase and in the oil phase. Therefore, phase quantification in vitro cannot simulate the dynamics of in vivo absorption events following application of a poorly water-soluble drug in a lipid vehicle.