The in vivo effects of gavage administration of the synthetic, functional biomimetic cation [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+) to healthy and type 2 diabetic model rats are described. After 24 weeks of treatment (0-1,000 microg Cr/kg body mass) of healthy Sprague Dawley rats, the cation results in a lowering (P < 0.05) of fasting blood plasma low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and insulin levels and of 2-h plasma insulin and glucose concentrations after a glucose challenge. Zucker obese rats (a model of the early stages of type 2 diabetes) and Zucker diabetic fatty rats (a model for type 2 diabetes) after supplementation (1,000 microg Cr/kg) have lower fasting plasma total, high-density lipoprotein, and LDL cholesterol, triglycerides, glycated hemoglobin, and insulin levels and lower 2-h plasma insulin levels in glucose tolerance tests. The lowering of plasma insulin concentrations with little effect on glucose concentrations suggests that the supplement increases insulin sensitivity. The cation after 12 and 22 or 24 weeks of administration lowers (P < 0.05) fasting plasma glycated hemoglobin levels in the Zucker diabetic and Zucker obese rats, respectively, and thus can improve the glucose status of the diabetic models. The effects cannot be attributed to the propionate ligand.

The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (C max ) ؎ standard error of the mean increased from 16.01 ؎ 0.61 g/ml at the 1-mg/kg dose to 105.52 ؎ 8.92 g/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 ؎ 2.37 to 158.43 ؎ 15.58 g ⅐ h/ml, respectively. The mean apparent volume of distribution at steady state (Vd ss ) was 0.299 ؎ 0.011 liter/kg at the 1-mg/kg dose and 0.351 ؎ 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 ؎ 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 ؎ 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increased Vd ss , there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi.Caspofungin (MK-0991) is a novel, investigational parenteral antifungal agent that belongs to a new generation of semisynthetic cyclic lipopeptides of the echinocandin family. It acts by noncompetitive inhibition of the synthesis of 1, 3-␤-Dglucan, an essential homopolysaccharide in the cell wall of many pathogenic fungi (11,13). Similar to other current investigational echinocandin derivatives, caspofungin has potent and fungicidal in vitro activity against most clinically relevant Candida species without cross-resistance to currently approved antifungal agents, and it has cell-wall damaging effects on several Aspergillus species (3,6,8,9,15,16,20). The drug has demonstrated very promising activity in infection models of oropharyngeal

J Biol Inorg Chem (2005) 10:119The authors wish to acknowledge that one author (JBV) is the inventor or co-inventor of four patents on the use of Cr oligopeptides and synthetic complexes as nutritional supplements and therapeutic agents.The online version of the original article can be found at http:// dx